Immuno doi: 10.3390/immuno6030057

Authors: Aleksandra Stajić Selena Zečević Jelena Sotirović Danilo Vojvodić Snežana Babac Aleksandar Perić

Background/Objective: Previous studies on the association between chronic rhinosinusitis (CRS) and allergic rhinitis (AR) have mostly focused on the general population, and much less on patients with CRS requiring surgical treatment. This study aimed to investigate the frequency of perennial and seasonal AR (PAR and SAR, respectively) among CRS patients in whom it was necessary to apply surgical treatment, including those with nasal polyps (CRSwNP) and those without (CRSsNP). Methods: A three-year retrospective study from a single center included CRS patients with indications for surgical treatment. The patients were not previously treated surgically. Several clinical parameters were considered: frequency of AR, PAR, SAR, SAR+PAR, asthma, and gastroesophageal reflux disease (GERD). Total serum IgE, percentage of eosinophils in peripheral blood, and Lund–Mackay computed tomography (CT) score (LMS) were also determined. Correlation analyses were performed to assess the relationships among the clinical parameters, while multivariable binary logistic regression analysis was performed to determine their independent associations with the outcome and to identify the best independent predictor. Results: A total of 155 patients with CRS were considered. Over 70% were patients with CRSwNP. AR was significantly more prevalent in patients with CRSwNP (p = 0.049), with PAR being the more common form (p = 0.035). Also, GERD and asthma were more common in CRSwNP (p = 0.01 and p = 0.001, respectively). The strongest correlation was found between total serum IgE and percentage of eosinophils (rho = 0.776; p < 0.001), then between percentage of eosinophils and LMS (rho = 0.760; p < 0.001), as well as between total IgE and LMS (rho = 0.695; p < 0.001). Binary logistic regression analysis identified LMS as the only independent statistically significant predictor for CRSwNP (OR = 1.381, p < 0.001) among all numerical parameters. Conclusions: The results suggest a better association between PAR and CRS, especially with CRSwNP. Asthma and GERD are also highly associated, primarily with CRSwNP. LMS is the best independent predictor for the presence of CRSwNP.

Immuno doi: 10.3390/immuno6030056

Authors: Anastasia Malek Lidia Zabegina Alexander Garanin Tatiana Sharonova Asel Kudaibergenova Vladimir Evtushenko George Prokhorov

Although cryoablation of tumor tissue is known to induce systemic antitumor immune responses, the underlying mechanisms remain poorly understood, and therapeutic efficacy is often unpredictable. During cryoablation, the cryoprobe creates a temperature gradient, resulting in a central zone of lethal tissue destruction and a periphery characterized by sub-lethal injury. In this peripheral zone, cells undergo programmed cell death triggered by thermal shock and ischemia. A widely cited, yet debated, hypothesis suggests that these apoptotic events in the tumor periphery may suppress the antitumor immune response. The purpose of this study was to experimentally test this hypothesis. We utilized the murine breast cancer cell line (4T1-Luc) and a panel of human cell lines (MCF-7, BT-20, BT-474, MDA-MB-231, MDA-MB-453, HBL-100). Following validation via flow cytometry using Annexin V-AF488, Rhodamine 123, TMRE, PI, and 7-AAD, we established −7 °C and −80 °C as temperature conditions that predominantly induce apoptosis and necrosis, respectively. These conditions were used to prepare cryo-treated 4T1-Luc cells for the vaccination of syngeneic mice. Ten days post-immunization, the efficacy of the treatment was evaluated in subcutaneous solid tumor and lung metastasis models by monitoring tumor growth, quantifying tumor-specific antibodies, performing histological analysis of tumor and lung tissues, and quantifying lung metastases via PCR and luciferase assays. Contrary to the initial hypothesis, our findings demonstrate that tumor cells undergoing sub-lethal cryoablation do not acquire immunosuppressive characteristics. Instead, they promote systemic antitumor immunity. Although antitumor immunity induced by apoptotic and necrotic tumor cells was comparable in a subcutaneous tumor model, vaccination with necrotic tumor cells proved more effective than vaccination with apoptotic cells in controlling lung metastasis formation.

Immuno doi: 10.3390/immuno6030055

Authors: Manabu Mogitate

Chronic nasopharyngeal inflammation represents a state of persistent mucosal immune dysregulation within the nasopharynx, a key inductive site of upper airway immunity. In this review, we propose a hypothesis-generating conceptual framework in which disease progression reflects a sequential shift in dominant immune pathways—from early CD4+ T-cell-driven activation, through to T helper 17 (Th17)-mediated epithelial barrier dysfunction, and ultimately to CD8+ T-cell-mediated cytotoxic injury. These transitions are characterized by dynamic alterations in CD4/CD8 and Th17/Treg balance, contributing to epithelial fragility and sustained inflammatory activity. Beyond local pathology, prolonged inflammation may engage neuro-immune circuits, including vagal and neuroendocrine pathways, potentially linking mucosal immune activation to systemic physiological dysregulation. While several elements of this model are supported by existing knowledge in mucosal immunology, the integration of local and systemic immune processes remains partly hypothetical and requires further experimental validation. Epipharyngeal Abrasive Therapy (EAT) may represent a potential intervention within this framework, although its immunological mechanisms remain incompletely understood. However, the underlying mechanisms and clinical efficacy of EAT remain to be fully elucidated. This framework integrates local mucosal immune dynamics with potential systemic consequences and provides a conceptual basis for future investigations into chronic mucosal inflammation. It is intended as a hypothesis-generating conceptual review that integrates existing observations and proposes a conceptual framework to guide future mechanistic and clinical studies.

Immuno doi: 10.3390/immuno6030054

Authors: Maja Stojanovic Zikica Jovicic Ana Drazic Dusan Popadic Emina Milosevic

Background: Takayasu arteritis (TA) is a large-vessel vasculitis with an incompletely understood pathogenesis, in which genetic factors are thought to play an important role. Cytokine-mediated immune pathways, particularly those involving Th1 and Th17 responses, have been implicated in the immunopathogenesis of TA, making cytokine gene polymorphisms plausible genetic susceptibility markers. Methods: Functional single-nucleotide polymorphisms in selected cytokine- and receptor-encoding genes (IL12B, IL23R, IL6, TNF, IL10, and CSF2) were analyzed in 33 patients with TA and 486 healthy Serbian controls using TaqMan genotyping assays. Allele and genotype frequencies were compared between groups. Results: A nominally significant association was observed only for IL12B rs3212227. The T allele and TT genotype were less frequent in patients compared with controls (71.21% vs. 82.02%, p = 0.037; 48.48% vs. 66.67%, p = 0.041, respectively), suggesting a potential protective effect. No significant associations were detected for polymorphisms in IL23R, IL6, TNF, IL10, or CSF2. Conclusions: Our findings support the potential role of IL12B in genetic susceptibility to Takayasu arteritis, while other examined cytokine gene polymorphisms showed no statistically significant association. These results highlight the importance of the IL-12/IL-23 axis in disease pathogenesis and suggest possible population-specific genetic effects. Further studies in larger and independent cohorts are warranted to validate these findings.

Immuno doi: 10.3390/immuno6030053

Authors: Nan Li Shaochen Jiang Zhe Ding Weiwei Ju Fan Zhang Danni Mu Shengjin Yu Lijuan Lin

Background: Cyclophosphamide (CTX)-induced immunosuppression involves systemic toxicity, splenic atrophy, and broad transcriptomic disruption. Icariin (ICA) has immunomodulatory activity, but the systems-level features associated with splenic recovery remain incompletely defined. Methods and Results: Male mice were assigned to control, CTX, and CTX plus ICA (20, 40, or 80 mg/kg) groups. Phenotypic measurements were integrated with splenic RNA sequencing, differential expression analysis, targeted gene-set analysis, and weighted gene co-expression network analysis (WGCNA). ICA produced dose-associated improvement in spleen index and body weight trajectory, with the most consistent phenotypic response at 80 mg/kg. Overall transcriptomic separation was supported by permutational multivariate analysis of variance (PERMANOVA) (F = 17.18, R2 = 0.873, p < 0.001). WGCNA identified a recovery-associated turquoise module; Myb was assigned to this module, whereas Gata1 belonged to a distinct royalblue module. Complement and chemokine gene sets provided the strongest targeted enrichment evidence, and reverse transcription quantitative polymerase chain reaction (RT-qPCR) confirmed dose-associated changes in selected innate immune transcripts. Marker-based lineage signatures indicated non-uniform recovery, including persistent depression of the B-cell signature. Conclusion: ICA-associated phenotypic recovery coincided with partial, non-uniform remodeling of splenic transcriptional programs. The Myb- and Gata1-associated findings are hypothesis-generating co-expression signals and do not establish transcription-factor binding or causality.

Immuno doi: 10.3390/immuno6030052

Authors: Raghad Saeed Asiri Khaled Abdulwahab Amer Najla Al-Jahash Faisal Alhudaithi Rawan Abdullah Alqahtani Amjad Saad Alali

Background: Dedicator of cytokinesis 8 (DOCK8) deficiency is an autosomal-recessive combined immunodeficiency marked by severe cutaneous viral infections, atopy with elevated IgE, malignancy, and early mortality without hematopoietic stem-cell transplantation (HSCT). Foundational syntheses predate the current transplant era and biologic therapy. Objective: It aims to provide an updated individual-patient-data (IPD) synthesis of DOCK8 deficiency cases reported from 2017 to 2026. Methods: Following PRISMA 2020 and PRISMA-IPD guidance, we searched PubMed/MEDLINE (with full Boolean strings provided for Embase, Scopus, Web of Science and Cochrane CENTRAL) for reports with extractable individual data on confirmed DOCK8 deficiency. Two-stage screening, Murad-2018 risk-of-bias assessment, random-effects Freeman–Tukey pooled proportions (with a random-intercept logistic model as a sensitivity analysis), and reconstructed Kaplan–Meier analyses were performed. Results: Of 360 records, 56 full texts were assessed, and 41 studies were included; 29 provided individual data for 64 patients from 22 countries, and 12 contributed aggregate data. Sixty-three potentially eligible reports were paywalled and could not be retrieved, and non-English reports were excluded, introducing possible retrieval and language bias. Consanguinity was reported in 40/43 (93%); the genotype spectrum was dominated by large deletions and splice/intronic variants. Eczema (72%), cutaneous viral infection (80%) and bacterial infection (64%) predominated. The pooled proportion alive at last reported follow-up was 87.3% (95% CI 81.1–92.6); this is a cross-sectional proportion over variable follow-up and is not a long-term survival estimate, as reconstructed age-specific Kaplan–Meier survival fell to approximately 53% by age 20 (exploratory analysis). Pooled malignancy prevalence was 10.6% (95% CI 3.4–20.7; I2 = 66%), and pooled post-HSCT survival was 86.3% (95% CI 79.0–92.5). Conclusions: Contemporary reports reaffirm the severe infectious and malignant burden of DOCK8 deficiency and support HSCT as definitive therapy, alongside emerging biologic (dupilumab, siltuximab) and gene-directed strategies. Findings are constrained by reporting, retrieval and language bias and by reconstructed IPD; completion of the planned multi-database searches and independent second-reviewer verification are ongoing to finalise the evidence base.

Immuno doi: 10.3390/immuno6030051

Authors: Francesco Lanza Evita Massari Barbara Castagnari Martina Cantelli Giorgio Zavagli

PNH is an acquired ultrarare disease caused by a somatic mutation of PIGA gene located at band 22 of the short arm of the X chromosome, which is unable to carry out the synthesis of glycosil-phosphatidyl-inositol. The loss of complement regulators CD55 and CD59 is associated with the lack of the protective complement regulators in RBCs that become highly susceptible to complement-mediated lysis. PNH is characterized by intravascular hemolysis, high prevalence of thrombotic events, and a variable degree of bone marrow failure. It may arise from aplastic anemia, myelodysplasia and myeloproliferative neoplasms. Recently, a new clinical variant of PNH has been reported, the so-called “ahemolytic white blood cell PNH”, which may be associated with thrombotic episodes. In 2006, the introduction of eculizumab therapy has revolutionized the treatment for PNH patients. More recently, ravulizumab, crovalimab, iptacopan, danicopan, and pegcetacoplan have been introduced in the marketplace, with short/medium-term data supporting their safety and effectiveness. However, no trial has directly compared the clinical outcomes of the new drugs, and also the inclusion criteria in the various phase 3 trials were different, making a comparison between them difficult and unsatisfactory. It is conceivable that artificial intelligence and machine learning-based scoring models may be crucial for predicting the effectiveness of the anti-complement therapy.

Immuno doi: 10.3390/immuno6030050

Authors: Yumna A. Butt Nordin D. Zandhuis Iosifina P. Foskolou

RNA modifications act as crucial post-transcriptional regulators that fine-tune gene expression to modulate cell function. Among these, N6-methyladenosine (m6A) is the most prevalent RNA modification in eukaryotic cells, regulating several RNA metabolism pathways including RNA splicing, nuclear export, stability, and translation. These processes are particularly important in rapidly responding immune cells such as T cells, which require dynamic changes in gene expression to support differentiation and effector function. This review focuses on the interplay between immunity and epitranscriptomics and explores the direct and indirect effects of m6A modification on T cells. Specifically, we discuss the role of different writers, erasers, and readers in modulating CD4+ and CD8+ T cell homeostasis, differentiation, and function. In addition, we summarize current evidence linking m6A regulators to anti-tumor T cell responses. Finally, we discuss the recent advances in the field of m6A and immunotherapy by highlighting the potential of pharmacological modulation of m6A regulators in augmenting the efficacy of existing immune therapies. Collectively, by integrating emerging mechanistic and translational insights, this review highlights the pivotal role of m6A regulation in T cell biology and underscores its potential to optimize next-generation immunotherapies.

Immuno doi: 10.3390/immuno6030049

Authors: Ekaterina A. Botchkova Alexey V. Churov Mikhail S. Arbatskiy

Regulatory CD4+ T cells (Tregs) are essential for immune tolerance, tissue repair, and control of inflammation, but functional human Tregs cannot be identified reliably by a single protein. This targeted narrative review evaluates protein-level and proteomics-supported Treg signatures with explicit attention to species, sample source, analytical platform, validation strategy, and intended use. Primary human LC-MS/MS studies reveal pathway-level differences involving T-cell receptor signaling, metabolism, lysosomal activity, and lineage protection, whereas murine proteomic studies provide mechanistic candidates such as Themis1 but do not establish human biomarkers. CyTOF, functional single-cell protein profiling, spatially resolved protein imaging, and multi-omics further resolve phenotypic and tissue heterogeneity. Established CD25high/CD127low/FOXP3-based panels support enrichment and phenotyping; CTLA-4, ICOS, TIGIT, GITR, PD-1, chemokine receptors, suppressive enzymes, metabolic proteins, and emerging candidates report functional or tissue states but are not Treg-exclusive. Cancer currently provides the strongest tissue-level and prognostic evidence, whereas data in healthy aging, cardiovascular and metabolic disease, osteoarthritis, and neurodegeneration remain heterogeneous and mainly exploratory. Across contexts, validated diagnostic sensitivity, specificity, reference ranges, prospective clinical utility, and inter-laboratory reproducibility are largely absent. Treg immunoproteomics is therefore best regarded as a discovery and stratification framework rather than a standardized clinical diagnostic test.

Immuno doi: 10.3390/immuno6030048

Authors: Mariam Hassan Amjed Alsultan Dhama Alsallami Behrooz Sadeghi Kalani

Neonatal calf diarrhea (NCD) is one of the most important problems of calf breeding across the world. It causes deaths in calves in the first 10 days of their life, and it is mainly caused by Escherichia coli(E. coli), Bovine Rotavirus (BRV) and Bovine Coronavirus (BCoV). The lack of vaccines with consistently high protective efficacy against the main causes of NCD makes disease control highly challenging. The current study aims to design a multi-epitope mRNA-based vaccine targeting the major pathogens responsible for NCD using immunoinformatic tools and molecular modeling approaches. BRV capsid protein VP6, BCoV Spike glycoprotein and E. coli F5 fimbrial protein were used as antigenic proteins to predict potential epitopes. Fifteen selected epitopes were linked with suitable linkers and conjugated with a built-in adjuvant, resulting in the design of a stable, antigenic and non-allergenic vaccine candidate against NCD pathogens. Furthermore, molecular docking analysis shows strong binding affinity between the vaccine candidate and the bovine toll-like receptors TLR2 and TLR4 at low energy and high stability. Based on these findings, the proposed multi-epitope vaccine represents a promising approach for the prevention and control of neonatal calf diarrhea and provides a solid scientific foundation for future experimental studies to validate its efficacy and safety in vivo.

Immuno doi: 10.3390/immuno6030047

Authors: Kazuhiro Kakimi Yukari Kobayashi Koji Nagaoka

Immune checkpoint inhibitors (ICIs) are now being introduced into perioperative treatment for several solid tumors. This strategy is usually explained by tumor reduction before surgery or by the elimination of minimal residual disease (MRD) after surgery. However, these explanations may not be sufficient to understand why the timing of ICI treatment, especially before lymph node (LN) removal, is important. In this review, we discuss tumor-draining lymph nodes (tdLNs) from two different aspects. tdLNs are anatomical routes for regional and distant metastasis, but they are also sites where tumor antigens are presented and tumor-specific T cell responses are generated. In particular, preclinical and translational studies suggest that tdLNs may maintain stem-like or progenitor-exhausted T cells (TPEX) that can respond to PD-1 blockade and supply more differentiated exhausted T cells to tumor sites. However, current clinical trials of perioperative ICIs demonstrate therapeutic benefit in specific diseases and regimens, but do not directly establish tdLN preservation or tdLN-resident TPEX maintenance as the decisive mechanism of efficacy. We therefore present the tdLN-reservoir model as a hypothesis-generating framework rather than as a clinically validated basis for modifying lymph node management. We also discuss the possible roles of neoadjuvant and adjuvant ICI in relation to antigen flow, minimal residual disease, metastatic-site draining LNs, postoperative lymphatic dysfunction, and future immune-guided clinical trials. Importantly, current evidence does not support altering standard lymph node surgery or radiotherapy solely to preserve putative tdLN immune-reservoir function.

Immuno doi: 10.3390/immuno6030046

Authors: Margarita Ruseva Teodora Tihomirova Dimitar Parvanov Rumiana Ganeva Maria Handzhiyska Jinahn Safir Sofia Koristashevskaya Ivan Pavlov Dimitar Metodiev Blaga Rukova Georgi Stamenov Savina Hadjidekova

The endometrial microbiome has been implicated in implantation success, and intrauterine peripheral blood mononuclear cell (PBMC) therapy has been proposed to improve endometrial receptivity; however, its effects on the endometrial microbial environment remain poorly understood. This prospective study evaluated changes in endometrial microbiome composition following PBMC therapy in 26 in vitro fertilization (IVF) patients. Paired endometrial biopsies were collected before and after intrauterine administration of autologous PBMCs, and 16S rRNA gene sequencing (V4–V5 region) was performed. Microbiome composition was analyzed at genus and species levels, and alpha and beta diversity metrics were compared between paired samples. No significant changes in microbial composition or diversity were observed across the entire cohort following treatment. However, patients with lower baseline Lactobacillus abundance exhibited greater microbiome responsiveness, showing larger increases in Lactobacillus after treatment. This association remained significant after adjustment for age and BMI (ρ = −0.457, p = 0.019; β = −0.367, p = 0.047). Moreover, subgroup analysis identified two distinct response patterns based on Lactobacillus dynamics: a Lactobacillus-increase group (n = 14) and a no-increase group (n = 12). Baseline Lactobacillus dominance (LD: >90% relative abundance) was less frequent in the increase group (14%) than in the no-increase group (50%). In Lactobacillus-increase patients, the median relative abundance rose from 17.6% to 95.5% (p < 0.001), 64% achieved LD, and Shannon and Simpson diversity indices decreased significantly (p = 0.04 and p = 0.02, respectively). In the no-increase group, Lactobacilli remained the most abundant taxon, and the diversity indices were unchanged following treatment. These findings suggest that baseline endometrial microbiome composition may influence responsiveness to PBMC therapy and could support future patient stratification strategies in IVF treatment. Whether these microbiome changes translate into improved clinical outcomes requires evaluation in future studies.

Immuno doi: 10.3390/immuno6030045

Authors: Sotiris Kyriakou Argyris Kyriakou Marilina Neokleous Eren Ozan Bakır Petros Agathangelou Filippos Triposkiadis Gönül Zeren Panos Georghiou Georgios P. Georghiou

Percutaneous coronary intervention (PCI) treats focal coronary obstruction by compressing plaque, injuring the vessel wall, and placing a metallic or bioresorbable scaffold. Most treated segments heal, but a small minority enter a prolonged, excessive, or unstable repair state that contributes to in-stent restenosis (ISR), in-stent neoatherosclerosis, and stent thrombosis (ST). Human evidence is strongest for delayed healing, uncovered struts, macrophage-rich neoatherosclerosis, and hypersensitivity-associated late thrombosis, whereas routine immune biomarker-guided care remains unsupported. The practical question addressed here is therefore not whether inflammation participates, which is established, but which immune signals, read together with intravascular imaging, could realistically change post-PCI management. The narrowed lumen is only the visible endpoint; beneath it sits vascular repair shaped by device-material exposure, local haemodynamics, and host immunity. Endothelial denudation and platelet activation initiate fibrin deposition, complement signalling, and release of damage-associated molecular patterns (DAMPs). Neutrophils, monocytes, and macrophages dominate early, followed by lymphocytes and vascular smooth muscle cells that remodel the repair compartment. Drug-eluting stents (DES) have markedly reduced early neointimal hyperplasia, yet selected late failures still involve delayed endothelial recovery, chronic peristrut inflammation, hypersensitivity, and neoatherosclerotic transformation. Immune biology is useful at the bedside only when interpreted with procedural context, device design, and patient phenotype. Imaging-defined endpoints and paired immune phenotyping are therefore needed to guide treatment by mechanism instead of angiography or isolated biomarkers.

Immuno doi: 10.3390/immuno6030044

Authors: Waldir da Silva Rios Júnior Adenilda Cristina Honorio-França Kênia Maria Rezende Silva Danielle Cristina Honorio França Danny Laura Gomes Fagundes-Triches Aron Carlos de Melo Cotrim Edson Fredulin Scherer Dênia Mendes de Sousa Valladão Alda Maria Teixeira Ferreira Eduardo Luzía França Elton Brito Ribeiro

Chagas disease is a parasitic infection caused by Trypanosoma cruzi and remains an important public health problem with changing epidemiological patterns. Both the acute and chronic phases pose diagnostic and prognostic challenges due to the disease’s heterogeneous clinical course. Chronic inflammation and fibrosis associated with Chagas disease lead to anatomical and morphological changes, as well as increased release of inflammatory mediators. These factors may contribute to alterations in blood viscosity and hemorheological behavior. This study aimed to evaluate hemorheological properties and inflammatory cytokine levels in individuals with chronic Chagas disease. Blood samples from 18 individuals infected with T. cruzi and 15 uninfected controls were analyzed. Rheological parameters were measured using a rheometer, and cytokine levels were quantified by flow cytometry. The infected group had a mean age of 57.25 years, including both sexes. The mean time since laboratory diagnosis was 13 years. Hematological analysis demonstrated significant alterations in leukocyte subpopulations and erythrocyte-related parameters, including lymphocyte count, red blood cell indices, hemoglobin, hematocrit, and platelet-related markers. Blood samples from both groups demonstrated non-Newtonian fluid behavior and non-linear flow curves. However, individuals infected with T. cruzi presented significant alterations in blood viscosity compared to controls. Increased serum levels of IL-1β, IL-6, CXCL8 (IL-8), and IL-10 were also observed in infected individuals. The blood viscosity showed a significant positive correlation with CXCL8 (IL-8) and IL-10 levels. These findings suggest that cytokine-associated hemorheological alterations may contribute to the pathophysiology and clinical progression of chronic Chagas disease.

Immuno doi: 10.3390/immuno6030043

Authors: Nathalia Estefany Patiño Rodríguez Jaqueline Mena Huertas Orfa Alexandra España Jojoa Andrés Mauricio Hurtado Benavides

Background: Neutrophil dysregulation drives inflammatory pathologies through mechanisms such as matrix metalloproteinase-9 (MMP-9) release. High-value bioprospecting of agro-industrial residues offers a sustainable strategy to identify novel bioactive compounds. In this study, the immunomodulatory effects of seed oils (SOs) obtained via supercritical fluid extraction from Passiflora edulis and Rubus glaucus byproducts on human neutrophil responses was evaluated. Methods: SO lipid profiles were characterized via GC-MS. Human neutrophils were isolated using Percoll gradients and treated with the SOs (10–50 µg/mL). Cytocompatibility was assessed via MTT and trypan blue assays. MMP-9 activity and ERK1/2/p38 phosphorylation were determined via zymography and Western blotting, respectively. Results of GC-MS revealed matrices rich in unsaturated lipids: R. glaucus SO was dominated by linoleic (50.02%) and α-linolenic (29.84%) acids, whereas P. edulis SO contained linoleic (58.91%) and oleic (19.75%) acids. Both oils were highly biocompatible up to 50 µg/mL. Both SOs significantly increased MMP-9 release; notably, R. glaucus induced a dose-dependent response and a potential priming effect at 10 µg/mL. Interestingly, neither oil induced the phosphorylation of ERK1/2 or p38. Conclusions: Supercritical fluid-extracted SOs from P. edulis and R. glaucus byproducts modulate early neutrophil responses by increasing MMP-9 release through pathways independent of classical MAPK phosphorylation. Further functional and in vivo validation is needed to clarify the precise regulatory roles of these specialized lipid matrices in human inflammation resolution and their potential as bioactive ingredients for nutraceutical or pharmaceutical applications.

Immuno doi: 10.3390/immuno6030042

Authors: Derek Gu Vincent Yuan

Circadian rhythms impose temporal organization on immune function, shaping host responses to infection, injury, and chronic disease. While transcriptional control by core clock components such as CLOCK and BMAL1 has been extensively characterized, this paradigm alone cannot explain the rapid and dynamic nature of immune signaling. Emerging evidence identifies post-translational modifications (PTMs)—including phosphorylation, ubiquitination, and acetylation—as critical regulators that confer speed, reversibility, and specificity to inflammatory pathways. Here, we propose the concept of a “Chrono-PTM axis,” in which circadian timing and PTM-dependent signaling are functionally integrated to govern immune activation thresholds. We discuss how PTMs not only regulate core clock machinery but also temporally gate key innate immune pathways, including NF-κB signaling and inflammasome activation, thereby controlling cytokine production at multiple levels. Furthermore, we highlight the role of immunometabolism in supplying essential cofactors that couple cellular energetic states to PTM dynamics, linking metabolic oscillations to inflammatory outputs. Disruption of this axis contributes to the pathogenesis of autoimmune diseases, cancer, and tissue-specific inflammatory disorders. Finally, we outline emerging therapeutic opportunities targeting the Chrono-PTM axis, including chronotherapy and PTM-directed interventions, and identify critical gaps in temporal proteomics and translational studies. Elucidating the integration of circadian and post-translational regulation will provide a unifying framework for understanding immune homeostasis and may enable time-informed precision immunotherapy.

Immuno doi: 10.3390/immuno6020041

Authors: Analía Rial María Paula Céspedes Victoria Comas Mariana Rivera-Patrón Juan Martín Marqués José Alejandro Chabalgoity

Streptococcus pneumoniae is a leading cause of community-acquired pneumonia, yet the immune mechanisms required for protection against invasive pulmonary infection remain inadequately understood. Using a murine model of homologous protection against invasive pneumococcal pneumonia, we explored the relative contributions of humoral and cellular immunity using adoptive serum transfer, immune cell depletion, and lung transcriptional profiling. Our findings indicated that passive transfer of immune serum provided robust protection, while neutrophil depletion significantly compromised bacterial control, highlighting that both antibodies and neutrophils are key mediators of protection. In contrast, depletion of CD4+ T cells or NK cells did not compromise survival. Although IL-17A has been widely implicated in host defense against pneumococcal infection, IL-17A-deficient mice remained protected, albeit with delayed clearance and reduced early antibody responses. We associate this delay with compensatory upregulation of IL-17F and increased expression of Th1-associated genes in the lungs. Together, these findings indicate that IL-17A is not essential for protection and support a model in which coordinated Th1- and Th17-related cytokine responses collectively promote neutrophil recruitment and effective antibody-mediated defense. These results highlight functional redundancy within the IL-17 cytokine axis and suggest that integrated cytokine networks, rather than individual mediators, underpin protective immunity to pneumococcal pneumonia, with implications for next-generation vaccine design.

Immuno doi: 10.3390/immuno6020040

Authors: Andrea Emanuele Guerini Sara Pedretti Althea Carlino Marta Maddalo Eneida Mataj Ludovica Pegurri Gianluca Cossali Paolo Borghetti Giorgio Facheris Luca Nicosia Chiara Valietti Marco Lorenzo Bonù Luca Triggiani Michela Buglione di Monale e Bastia

Background: A combination of cyclin-dependent kinase 4/6 inhibitors (CDKi) and radiotherapy (RT) may enhance antitumoral immunity, yet clinical evidence of this interaction in HR+/HER2− metastatic breast cancer (MBC) remains limited. This study evaluates the impact of combined CDKi and stereotactic body radiotherapy (SBRT) on immune biomarkers and treatment response. Methods: We report a case of a 51-year-old woman with oligometastatic HR+/HER2− MBC involving the sacrum. Clinical management included letrozole plus palbociclib and SBRT (30 Gy in 3 fractions). Serial Neutrophil-to-lymphocyte ratio (NLR) measurements, MRI, and PET-CT scans were used to monitor systemic immune modulation and treatment efficacy over a five-year period. Results: Baseline NLR was 1.068. Following four weeks of CDKi, NLR decreased by 44.7% (0.591). Post-SBRT, a further 17.8% reduction was observed (nadir 0.486). Five months post-RT, MRI showed a volumetric increase in sacral lesions despite clinical improvement. Subsequent PET-CT demonstrated a complete metabolic response, confirming the MRI findings as pseudoprogression. As of January 2026, the patient remains in sustained complete metabolic remission. Conclusion: The integration of CDKi and SBRT might induce an immune-mediated antitumoral response, evidenced by dynamic NLR reductions and radiologic pseudoprogression. Multimodal imaging is essential to differentiate immune-mediated swelling from true progression in this setting.

Immuno doi: 10.3390/immuno6020039

Authors: Rumiana Ganeva Teodora Tihomirova Dimitar Parvanov Margarita Ruseva Maria Handzhiyska Stela Chapanova Dimitar Metodiev Maria Pancheva Maria Serafimova Rada Staneva Blaga Rukova Jinahn Safir Sofia Koristashevskaya Georgi Stamenov Savina Hadjidekova

The aim of this study was to investigate the association between the endometrial microbiome and local immune cell composition during the implantation window. We conducted a single-center prospective observational study including endometrial samples from 58 women without endometrial pathology. All samples were obtained during the mid-secretory phase (day 5 post-ovulation). Endometrial stromal CD3+ T cells, CD4+ T helpers, CD56+ NK cells and CD68+ macrophages were identified by immunohistochemistry and quantified as a percentage of stromal cells using HALO image analysis software. Microbiome composition was assessed by 16S rRNA gene sequencing (V4–V5 region). Lactobacillus dominance (LD) was defined as the genus with the highest centered log-ratio value within each sample. Endometrial immune cell composition showed a median 2.28% CD3+ T cells of stromal cells, 1.75% CD56+ NK cells, 1.44% CD68+ macrophages and 0.29% CD4+ T helpers. Lactobacillus-dominated microbiota was identified in 51.7% (30/58) of samples. Correlation analysis showed that Lactobacillus-related taxa were negatively associated with NK/T ratios and positively with T helper-related ratios. LD samples exhibited reduced NK cell abundance (1.17% vs. 2.12%, p = 0.006, q = 0.023) and a lower NK/T ratio (0.52 vs. 1.05, p = 0.004, q = 0.023) compared to non-LD samples. This study provides evidence for a link between microbial composition and local immune regulation in the endometrium.

Immuno doi: 10.3390/immuno6020038

Authors: Carlos M. Ardila Eliana Pineda-Vélez Anny M. Vivares-Builes Alejandro I. Díaz-Laclaustra

Oral squamous cell carcinoma (OSCC) shows substantial immune and clinical heterogeneity that is not fully captured by conventional clinicopathologic risk factors. This systematic review synthesized primary studies evaluating immune biomarker signatures in OSCC identified through spatial transcriptomics, single-cell transcriptomics, and artificial intelligence (AI)-enabled pathology. PubMed/MEDLINE, Scopus, and Embase were searched without language or date restrictions. Eligible studies included original human OSCC investigations reporting immune-relevant biomarker outputs derived from spatial/single-cell transcriptomics or AI-enabled pathology. Nine studies met the inclusion criteria. Six used spatial and/or single-cell transcriptomic approaches, and three used AI-enabled pathology applied to histopathological whole-slide images. Functional meta-synthesis identified four interconnected domains: AI-derived tissue immune infiltration for prognostic stratification; T-cell states and tertiary lymphoid structure-associated antitumor immunity; spatial and metabolic immunosuppressive niches; and stromal–myeloid programs linked to T-cell exhaustion and resistance. Quantitative synthesis was considered but not performed because no group of studies was sufficiently comparable in biomarker construct, comparator, outcome, and effect measure. Clinical confidence remains limited by heterogeneity and prospective validation gaps. These findings suggest that emerging OSCC immune biomarkers may integrate tissue architecture, cellular states, and stromal–immune interactions; however, the current evidence remains exploratory and requires standardized, prospective validation before clinical translation can be considered.

Immuno doi: 10.3390/immuno6020037

Authors: André Miller C. Lima Taciana Fernandes S. B. Coelho Carlos Alberto M. Carvalho

Lyssaviruses are neurotropic viruses that cause fatal encephalitis, with the rabies virus as the most prominent member. The viral glycoprotein (G) plays a key role in infection and is the main target of adaptive immune responses. This study aimed to comparatively analyze linear B- and CD4+ T-cell epitopes in the G protein ectodomain of lyssaviruses from phylogroups I (RABV, EBLV-1, EBLV-2, DUVV, and ABLV) and II (LBV and MOKV) using bioinformatics tools. Protein sequences were obtained from GenBank, processed to isolate ectodomains, aligned for identity analysis, and used to generate consensus sequences. CD4+ T-cell epitopes were predicted based on HLA-II binding affinity, while linear B-cell epitopes were identified using physicochemical properties and assessed for N-glycan masking. Amino acid identity ranged from 76.71% to 83.79% in phylogroup I and 82.72% in phylogroup II. Phylogroup I showed a higher density of HLA-II epitopes (0.22) than phylogroup II (0.18). Despite differences in antigenicity distribution, conserved linear B-cell epitopes in both phylogroups overlapped with peptides binding to HLA-II DRB1*15:01 and were not masked by N-glycans. These findings highlight putatively conserved antigenic regions identified through computational analysis and may support future studies focused on the development of improved vaccines and immunoprophylactic strategies against lyssaviruses.

Immuno doi: 10.3390/immuno6020036

Authors: Akshayaa Manikandan Charles Emmanuel Jebaraj Walter Sankari Durairajan Natarajan Kumaresan Anandan Balakrishnan Ashwini Saravanan Jezra Emmanuel Walter Thanka Johnson

Bladder cancer worldwide has seen a sharp rise, making it a significant global health concern. Recurrence monitoring is the main concern in treating the disease, and drug resistance follows suit. Treatment options include first-line medications, adjuvant therapy with BCG (Bacillus Calmette–Guérin) instillations, and combination therapies targeting the PD-1/PD-L1 axis. It has varying 5-year relative survival rates depending on the stage at diagnosis. Despite initial treatment success, resistance often develops, leading to relapse. Resistant to standard treatment is often due to immune landscape changes that are controlled by the most aberrant genes in bladder cancer, which also have a hold in the immune environment of the bladder. Dysregulation of FGFR3 (Fibroblast Growth Factor Receptor 3) in bladder cancer contributes to cell proliferation and metastasis. Simultaneously, the alterations in EGFR (Epidermal Growth Factor Receptor) regulation are linked to cell migration and resistance to treatment. FGFR3 in non-muscle invasive bladder cancer and EGFR in muscle-invasive bladder cancer are central elements in triggering various signaling pathways that contribute to chemoresistance. Concentrating the roles of both genes within the bladder tumour, they present opportunities not only as therapeutic targets but also as potential points of resistance and monitoring for recurrence. Exploring FGFR3 and EGFR to enhance treatment efficacy when combined with ICIs and developing markers into reliable diagnostic tools for recurrence, ultimately aiming for improved patient well-being, is the key aspect we propose to target from this narrative.

Immuno doi: 10.3390/immuno6020035

Authors: Mostafa F. Mohammed Saleh Ahemd Kotb Abrabou Abdulrahman Nasiri Alfadil Haroon Mahmoud Aljurf

Severe aplastic anemia (SAA) in pregnancy represents a rare but life-threatening clinical challenge. Standard therapies such as hematopoietic stem cell transplantation (HSCT) and immunosuppressive therapy are limited during pregnancy due to safety concerns, leaving supportive care as the mainstay. Thrombopoietin receptor agonists (TPO-RAs) such as eltrombopag have emerged as promising agents in refractory SAA, though evidence of their safety in pregnancy remains scarce. We present the case of a 27-year-old woman with SAA post-allogeneic bone marrow transplant who relapsed during subsequent pregnancies. Her disease course was characterized by recurrent pancytopenia, mixed chimerism, and repeated need for stem cell boosts. During pregnancy in 2023, discontinuation of cyclosporine led to worsening cytopenias, prompting reintroduction of cyclosporine and the continuation of eltrombopag. This combined approach, alongside G-CSF and stem cell boosts, contributed to favorable hematologic stabilization. She successfully delivered a healthy infant and achieved hematologic recovery following a third stem cell boost postpartum. This report highlights the potential utility of TPO-RAs during pregnancy when conventional therapy is limited, while emphasizing the need for vigilant monitoring of maternal–fetal outcomes. A review of the literature suggests that although routine use of eltrombopag in pregnancy is not recommended, it may be considered in refractory SAA cases with careful risk–benefit assessment. The case underscores the role of multidisciplinary care, individualized therapeutic planning, and the need for further studies on TPO-RAs in pregnancy-associated bone marrow failure syndromes.

Immuno doi: 10.3390/immuno6020034

Authors: Shukur Wasman Smail Abdullah Hayder Flaih Blnd Azad Ismail Akhter Ahmed Ahmed Ahmed Abdulrazzaq Bapir Fikry Ali Qadir Christer Janson

Living therapies, including chimeric antigen receptor T (CAR-T) cells, oncolytic viruses (OVs), and bacteria-based platforms, are emerging as promising approaches in cancer treatment because they can directly target tumors and modulate anti-tumor immunity. This narrative review summarizes current knowledge on these therapies, focusing on their mechanisms of action, therapeutic applications, major limitations, and recent advances in genetic engineering, synthetic biology, and delivery systems. CAR-T cell therapy has shown substantial clinical success in hematological malignancies through the genetic redirection of T cells against tumor-associated antigens, although its efficacy in solid tumors remains limited by antigen heterogeneity and the immunosuppressive tumor microenvironment (TME). OVs selectively infect and lyse malignant cells while also stimulating local and systemic immune responses, and engineered OVs may further enhance therapeutic activity by reshaping the TME. Bacteria-based therapies exploit the natural tumor-targeting ability of selected strains, particularly in hypoxic regions, to deliver therapeutic agents and activate immune responses. Despite encouraging progress, safety concerns, immune-related barriers, and tumor complexity remain major challenges. Overall, integrating living therapies with modern biotechnological advances and existing treatment modalities may support more personalized and synergistic strategies for cancer management.

Immuno doi: 10.3390/immuno6020033

Authors: Miguel Angel Carmona-Zamudio Francisco Sierra-López Carlos Emilio Miguel-Rodríguez Maricarmen Hernández-Rodríguez Gustavo Acosta-Altamirano Mónica Sierra-Martínez

Extracellular vesicles (EVs) are lipid bilayer-bound structures capable of transporting molecular markers from their cell of origin and are secreted by multiple cell types, including malignant cells. EVs have emerged as promising tools for developing less invasive diagnostic approaches. In B-cell acute lymphoblastic leukemia (B-ALL), immunophenotypic characterization of extracellular vesicle-enriched populations (EVEPs) in peripheral blood (PB) may provide complementary information for disease detection and monitoring. This exploratory study aimed to characterize EVEPs obtained from PB and bone marrow (BM) of adult patients with B-ALL and to compare them with the clinical immunophenotype (CIP). A total of 12 individuals were initially recruited (eight with B-ALL, one with T-ALL, and three healthy controls). The study focused on the eight B-ALL patients and three controls, while the T-ALL sample was used as a specificity control. EVEPs were isolated by differential centrifugation and analyzed by flow cytometry and confocal microscopy, primarily evaluating CD3 and CD19 expression. EVEPs derived from PB samples of patients with B-ALL showed a higher percentage of marker-positive events by flow cytometry (CD45, CD34, CD19, CD20, and CD10), consistent with the leukemic phenotype identified in the CIP. Additionally, CD3+CD19+ EVEPs were occasionally detected. These findings suggest that EVEPs partially reflect the leukemic immunophenotype and may serve as a complementary source of biological information. The detection of CD3+CD19+ events highlights complex cellular interactions within the leukemic niche and warrants further investigation.

Immuno doi: 10.3390/immuno6020032

Authors: Rebecca Sayuri Barbosa Hanada Antonia Maria Ramos Franco-Pereira Juliana Cavalcante de Araújo Laís Gomes da Silva Mayara Arguello da Silva Rafaela Benício Santana Sandra Tuye Velaca Claudio Lucas Santos Catão Estela Yasmin Coelho de Oliveira Yury Oliveira Chaves Allyson Guimarães da Costa Adriana Malheiro Alle Marie José Fernando Marques Barcellos Bruno Bezerra Jensen

Cutaneous leishmaniasis remains a therapeutic challenge due to toxicity, parasitic resistance, and the limitations of conventional drugs. In this context, combination therapies using natural immunomodulatory compounds have emerged as a promising alternative. This study evaluated the antileishmanial, cytotoxic, and immunomodulatory effects of gallic acid (GA) combined with paromomycin sulfate (PAR) using in vitro models. IC50 values were determined in promastigote and amastigote forms of Leishmania (Viannia) guyanensis, and CC50 values were assessed in RAW 264.7 macrophages. Peripheral blood mononuclear cells (PBMCs) from healthy volunteers (n = 13) were stimulated with GA, PAR, GA + PAR, or controls to evaluate lymphoproliferation and cytokine production. GA showed higher activity against intracellular amastigotes (IC50 = 11.4 µM), while GA + PAR also demonstrated activity (IC50 = 20.5 µM). PAR alone showed limited efficacy. The combination exhibited limited antiparasitic activity, with effects mainly at higher concentrations and without consistent superiority over GA monotherapy. Immunologically, GA + PAR displayed a balanced cytokine profile without inducing excessive proliferation. These findings suggest a complementary immunomodulatory effect, although further studies are needed to confirm its therapeutic relevance.

Immuno doi: 10.3390/immuno6020031

Authors: Muhammad Mujahid Amjed Khushi Muhammad Masood Rabbani Aman Ullah Khan Muhammad Mubashar Beig Muhammad Asad Ali

Foot-and-Mouth Disease (FMD) is caused by the FMD virus. Indirect Sandwich Enzyme-Linked Immunosorbent Assay (IS-ELISA) was standardized to characterize the FMD serotype “O” virus. Total protein content in the guinea pig serum (whole serum), ammonium sulfate precipitated guinea pig serum (ASPGPS) protein and ion-exchange-based purified guinea pig serum (IEGPS) protein was measured as 52 µg/mL, 24 µg/mL and 10 µg/mL respectively. The whole serum of guinea pigs and rabbits showed the 1:32 and 1:64 anti-FMD serotype “O” virus neutralizing antibody titers, while the anti-FMD serotype “O” virus neutralizing antibody titer was 1:128 in the IEGPS proteins. IEGPS protein with 1:128 neutralizing antibody titers were used as capture/trapping antibodies in the standardization of the assay. The IEGPS protein 1:1000 diluted with 10 µg/mL of protein content was found to be optimum for capture/trapping antibodies. To cover residual blank spaces, different available blocking buffers were evaluated and Skimmed Milk Solution 5% in Phosphate-Buffered Saline (PBS5%) proved best amongst blocking buffers. Coating of 1:1000 diluted IEGPS at 37 °C for 1 h followed by storage at 4 °C for overnight was best for incubation time. FMD serotype “O” virus 1:100 diluted was optimum in IS-ELISA. Similarly rabbit anti-FMD serotype “O” virus specific immune serum 1:10,000 diluted and goat anti-rabbit IgG horseradish peroxidase conjugate 1:4000 diluted were found to be optimum during the standardization of the assay. Lastly ELISA plates proved to be best amongst the available plates for assay. In each experiment, the plateau region, test background and plate background were recorded. Lastly it became possible for the establishment of an optimized and potentially cost-effective IS-ELISA requiring further diagnostic validation in research and diagnostic laboratories in the country.

Immuno doi: 10.3390/immuno6020030

Authors: Annette d’Arqom Kireina Azizah Rizky Nasya Malfa Aqilah Fathul Huda Ming Tatt Lee Belinda Anasthasya Tansy Suzita Mohd Noor Rimbun Ni Luh Ayu Megasari

Gabapentin is widely used for epilepsy and neuropathic pain. Beyond neurological indications, preclinical evidence suggests that gabapentin may exert anti-inflammatory effects that have not been systematically reviewed. A systematic review (2015–2025) was performed, resulting in thirteen in vitro and in vivo studies evaluating gabapentin’s impact on inflammatory signaling pathways, cytokine production, immune cell activity, and tissue inflammation. Outcomes included molecular pathways, inflammatory mediators, histopathological changes, and functional inflammatory measures. Risk of bias and study quality were assessed using the SYRCLE RoB tool for in vivo studies and the SciRAP approach for in vitro studies. Gabapentin demonstrated potential modulation of inflammatory responses in neuropathic pain, neuroinflammation, uveitis, and sepsis models through inhibition of MAPK and NF-κB signaling, reduction in pro-inflammatory cytokines, modulation of PPAR signaling pathways, and activation of Nrf2/HO-1 pathway. Gabapentin’s pharmacological actions extend beyond neuronal excitability to include modulation of inflammatory pathways, supporting a broader biological role for gabapentin. Although preclinical data support gabapentin’s potential anti-inflammatory properties, further targeted experimental and clinical studies are warranted to confirm these findings.

Immuno doi: 10.3390/immuno6020029

Authors: Rebecca R. Schmitt Sonali Garg Tracey A. Ignatowski Kathiravan Kaliyappan Vijaya Prakash Krishnan Muthaiah Paras N. Prasad Supriya D. Mahajan

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide, with blast TBI (bTBI) particularly affecting military personnel and individuals exposed to explosive environments, yet there are no available curative treatments to date. While adrenergic receptor antagonists have shown promise in reducing neuroinflammation and improving TBI mortality rates, systemic administration of these drugs can have deleterious effects including bradycardia and hypotension. Here, we introduce a polymeric nanoparticle system for the delivery of adrenergic receptor antagonists, which allows for size-based targeting of the injured blood–brain barrier (BBB). These nanoparticles consist of chitosan-coated polylactic co-glycolic acid encapsulating the β-adrenergic receptor antagonist propranolol and/or the α-adrenergic receptor antagonist phenoxybenzamine. Particles designed with a 200 nm hydrodynamic diameter showed a 20–24% increase in permeability on an in vitro contact co-culture BBB model exposed to a 23 or 35 PSI acoustic blast when compared to uninjured controls, whereas 100 nm particles show no difference, suggesting blast injury induces BBB damage that enables the accumulation of larger particles. Treatment of blast-injured human brain microvascular cells with our nanoformulation reduced extracellular inflammatory cytokine levels and reduced the expression of pro-inflammatory markers in microglia. Moreover, these particles mitigated the upregulation of extracellular TNFα induced by free phenoxybenzamine in injured and uninjured microglia, suggesting nanoparticle drug encapsulation can reduce adverse drug reactions in the brain. Together, these findings provide proof-of-concept for size-based targeting and the potential anti-inflammatory effects of CS-PLGA nanoparticles containing adrenergic receptor antagonists for treatment of TBI and bTBI.

Immuno doi: 10.3390/immuno6020028

Authors: Keren Grinberg

Chronic pain is increasingly understood as a neuroimmune disorder rather than a purely neuronal condition, in which immune mediators and immune-like signaling within the nervous system regulate nociceptive gain across peripheral tissues, dorsal root ganglia (DRG), spinal cord, and supraspinal networks. Seminal and recent syntheses show that microglia, macrophages, cytokines/chemokines, and innate immune sensors can initiate and maintain maladaptive plasticity and central sensitization, helping explain the frequent clinical dissociation between structural pathology, systemic inflammatory markers, and pain severity. However, immune biology is bidirectional: alongside pronociceptive pathways, a growing literature describes active “pain-resolving” programs that terminate sensitization and restore homeostasis, including regulatory T cell (Treg)–IL-10 signaling and specialized pro-resolving mediators (SPMs). A structured search of PubMed/MEDLINE, supplemented by Europe PMC and PubMed Central, was performed, and citation chasing through broad scholarly indices was used to identify high-impact reviews, meta-analyses, and translational mechanistic studies. Systematic biomarker syntheses in low back pain, neck pain, and fibromyalgia indicate modest and heterogeneous systemic inflammatory signals, underscoring the need for mechanistic endotyping and stage-specific interventions. Based on this evidence, a clinically oriented framework is presented that distinguishes immune-driven pain amplification from impaired resolution and outlines practical implications for assessment, biomarker interpretation, and precision-oriented trial design.

Immuno doi: 10.3390/immuno6020027

Authors: Lesly Cristel Jiménez Cabrera Pablo Alejandro Gamas-Trujillo César De los Santos-Briones Luis Sáenz-Carbonell Ignacio Islas-Flores Karla Gisel Carreón-Anguiano Roberto Vázquez-Euan Nuvia Kantún-Moreno Blondy Canto-Canché

Both plants and animals have developed a sophisticated two-tiered innate immune system. This involves an initial recognition of microbial patterns conserved on the cell surface (PAMP-triggered immunity) and a subsequent more specific intracellular recognition of pathogenic effectors or their activities (effector-triggered immunity). A common fundamental feature is the use of NLR-like intracellular receptors to detect insider threats. Both plant NLRs (receptors containing nucleotide-binding domains and leucine-rich repeats) and animal NLRs (NOD-like receptors) share a modular tripartite architecture, typically featuring a central nucleotide-binding domain (NBD/NOD) and C-terminal leucine-rich repeats (LRRs). The NBD/NOD is crucial for facilitating the exchange of ADP/ATP, acting as a molecular switch to promote oligomerization and activation of NLRs in both kingdoms. In this review, we summarize the similarities and differences between plant and animal molecular perception and immunity mechanisms. Additionally, we highlight the fact that some human pathogens can infect plants, and crucially, some plant pathogens are capable of causing disease in humans. This suggests conserved molecular strategies to invade and manipulate host cells belonging to different biological kingdoms, uncovering that plant and human pathology may benefit from future investigations in their respective fields.

Immuno doi: 10.3390/immuno6020026

Authors: Urooj Alam Kunal Chaudhary Nishant Kumar Ritu Tomer Sumeet Patiyal Gajendra P. S. Raghava

This manuscript presents an updated version of PEPlife, a manually curated database that provides extensive information on peptide half-life. The updated version, PEPlife2, contains 4500 total entries, including 2300 newly curated entries and 2200 entries from the previous PEPlife database. These entries correspond to 1673 unique peptide sequences and 257 unique protein sequences where different entries may refer to the same peptide/protein sequence, the half-life of which was evaluated using different experimental assays. Each entry contains detailed information, including experimental methods used to determine half-life, chemical modifications, biological activity, routes of administration, and other relevant data. In addition to unmodified peptide sequences, PEPlife2 includes cyclic peptides and chemically modified peptides, such as those with N- and C-terminal modifications. To provide structural insights, peptide and protein structures were sourced from the Protein Data Bank (PDB) or predicted using PEPstrMOD. PEPlife2 integrates advanced analytical tools including BLAST (version 2.7.1), Smith–Waterman and CLUSTALW. This database provides a valuable resource for peptide and protein therapeutics research, particularly in the design of immunotherapeutics and vaccines.

Immuno doi: 10.3390/immuno6020025

Authors: Xin Rong Lim Samuel Shang Ming Lee Justina Wei-Lynn Tan Sze-Chin Tan Bernard Pui Lam Leung

Hypersensitivity reactions to iodinated contrast media (ICM) are traditionally categorized as immediate or delayed reactions, involving IgE-mediated pathways, non–IgE-dependent mast cell or complement activation, or T cell–mediated immune mechanisms. However, we observed that some individuals develop systemic inflammatory responses that do not fit these established categories. We describe here a case series of three patients who developed cytokine release syndrome (CRS)-like reactions following iodinated contrast administration, which were initially difficult to distinguish from sepsis and were only recognized after recurrent episodes. Clinical presentation, laboratory findings, cytokine profiles, allergy investigations, and treatment outcomes were reviewed. All patients developed fever, rigors, and hypotension within 5 to 70 h after exposure, accompanied by leukocytosis and markedly elevated inflammatory markers despite negative microbiological investigations. Serum tryptase levels remained within the normal range with no significant rise, while cytokine analyses demonstrated elevations of pro-inflammatory interleukin-6 and other cytokines in patients 1 and 3 where samples were available. Standard corticosteroid premedication did not prevent recurrence, and one patient developed systemic symptoms following intradermal testing. All patients improved with high-dose systemic corticosteroids and supportive care. These findings suggest that ICM may induce a cytokine-mediated inflammatory phenotype distinct from classical hypersensitivity reactions, highlighting the importance of early clinical recognition to guide diagnosis and management.

Immuno doi: 10.3390/immuno6020024

Authors: Jaika M. I. Rutgrink Anje A. te Velde

Inflammatory bowel disease (IBD) is a chronic, immune-mediated gastrointestinal disorder. Although genetic susceptibility contributes to disease risk, it cannot explain the rapidly rising incidence, implicating environmental drivers. Diet has emerged as a key factor, especially the growing global consumption of ultra-processed foods (UPFs), characterised by extensive use of industrial food additives. While epidemiological studies increasingly associate UPF consumption with IBD risk, the underlying biological mechanisms remain insufficiently integrated. This review examines how UPF consumption contributes to IBD pathogenesis and whether dietary modification offers a more comprehensive therapeutic approach than immune inhibition alone. The evidence demonstrates that UPFs, particularly their additive components, disrupt gut homeostasis through converging mechanisms that closely align with IBD pathogenesis. By promoting dysbiosis, impairing mucus and epithelial barrier integrity, inducing endoplasmic reticulum stress, and activating inflammatory pathways such as the NLRP3 inflammasome, food additives sustain the self-perpetuating cycle of intestinal inflammation characteristic of IBD. Although immune dysregulation is central to disease expression, evidence indicates that it is largely driven by upstream disturbances in the gut environment. Current immune-targeted therapies control symptoms but do not address these upstream drivers. In contrast, dietary modulation, particularly reducing UPF exposure, offers a system-level strategy to restore gut homeostasis and complement existing treatments. Together, these findings support a shift in IBD research and management toward targeting upstream drivers of inflammation to improve long-term disease control and ultimately mitigate the growing global burden of IBD.

Immuno doi: 10.3390/immuno6020023

Authors: Olalekan Chris Akinsulie Sinem Ulusan Ibrahim Idris Sammuel Shahzad James Okon Chizaram Ukauwa Moyinoluwa Oladoye Victor Aliyu Charles Egede Ugwu Toyin Ayandokun Roberta Koku Jesuferanmi Mary Akinsulie Muhammad Ipoola Adeyemi Charity Chinonso Ugwu Lilian Chizobam Ugorji

Antibodies are highly specialized glycoproteins produced by B cells in response to antigenic stimulation. They are a major component of the adaptive immune system and play a key role in host defenses by detecting, neutralizing, and eliminating foreign antigens. Over the years, their roles have transcended mere immune biomarkers due to their unique specificity, affinity maturation, and structural versatility, making them indispensable tools in biomedical research, including vaccine design, therapeutic development, and diagnostics. In this work, we examine the structural and functional basis of antibody bioactivity while highlighting key engineering strategies, including Fc modification, glycosylation engineering, and the development of novel antibody formats. We also considered the application of engineered antibodies in infectious disease and cancer prevention and treatment, focusing on current challenges, and proposing emerging directions that position antibody engineering as a transformative approach in future biomedical research and innovation.

Immuno doi: 10.3390/immuno6020022

Authors: Tanvir Zaman Shoyshob Nusrat Afrin Md Minhajul Islam Mithila Farjana Md. Tarek Ahmed Roni Mithila Sen Mohammad Shafiul Azam Ajahar Islam Hridoy Akhi Moni Md Jamal Uddin

Kidney disease is an alarming universal health concern and a leading cause of morbidity and mortality. About 861 million individuals around the world suffer from kidney complications. However, current treatment alternatives are limited. These limitations underscore the urgent need for new therapeutic approaches. Autophagy is a dynamic and cellular housekeeping mechanism. The use of conditional autophagy-related gene knockouts in kidney cells has led to a better understanding of autophagy’s significance. Basal autophagy in the kidney serves as a quality control mechanism, vital for cellular metabolism and organelle homeostasis. Under stressful conditions, kidney cells adapt their autophagic activity. This process is intricately controlled by signaling pathways that control autophagic flux, with sirtuins, AMP-activated protein kinase (AMPK), and mammalian target of rapamycin (mTOR) acting as key regulators. Additionally, autophagy plays a role in the natural aging process of renal tissue. Small-molecule natural products have demonstrated efficacy in regulating autophagy and mitigating kidney damage in several experimental studies. However, specific mechanisms by which small molecules regulate autophagy across different renal disorders have yet to be fully understood. This study shows that the recent advancements in using small molecules in autophagy research have reignited interest in the related signaling pathways and their role in the pathophysiology of renal diseases. Further research on autophagy and its regulatory signaling networks could provide new therapeutic targets for small-molecule intervention in renal disorders.

Immuno doi: 10.3390/immuno6020021

Authors: Karina Trejo-Vázquez Carlos H. Espino-Salinas Jorge I. Galván-Tejada Karen E. Villagrana-Bañuelos Valeria Maeda-Gutiérrez Carlos E. Galván-Tejada Gloria V. Cerrillo-Rojas Hans C. Correa-Aguado Manuel A. Soto-Murillo

Melanoma is characterized by a high mutational burden making it an established model for studying tumor neoantigens and developing strategies for personalized immunotherapy. In this study, a reproducible bioinformatics pipeline was developed and implemented for the identification and prioritization of candidate neoantigens derived from non-synonymous somatic mutations in melanoma, using genomic data from the MSK-IMPACT cohort (mel-mskimpact-2020; n = 696) and comparative reference information from TCGA-SKCM. From the somatic mutation annotation file (MAF), 16,311 non-synonymous mutations were filtered, from which 50,480 mutant 8–11-mer peptides were generated using a sliding-window approach centered on the mutated position. Peptide–HLA class I binding affinity was predicted using MHCflurry 2.0 across six representative alleles (HLA-A*02:01, HLA-A*24:02, HLA-B*35:01, HLA-B*39:05, HLA-C*04:01, and HLA-C*07:02). Candidate prioritization was initially based on predicted binding percentile (rank ≤ 2), identifying 12,209 peptide–HLA combinations with high predicted binding affinity. To refine candidate selection, additional computational analyses were incorporated, including proteasomal cleavage prediction using NetChop 3.1 and estimation of T-cell epitope immunogenicity using the Immune Epitope Database (IEDB) immunogenicity predictor. Furthermore, a direct comparison between mutant (MUT) and corresponding wild-type (WT) peptides was performed using Δaffinity and Δrank metrics to evaluate the predicted impact of somatic mutations on HLA binding. The analysis revealed a predominance of peptides associated with the HLA-B locus, particularly the allele HLA-B*35:01, among the interactions with the lowest predicted binding percentiles. Several high-ranking peptide candidates were derived from genes with known roles in melanoma biology, including PLCG2, GATA3, AKT1, PTEN, PTCH1, and SMO. Overall, the integrative computational framework implemented in this study enables the systematic prioritization of candidate neoantigens derived from non-synonymous mutations in melanoma. This pipeline provides a reproducible strategy for exploring tumor neoantigen repertoires and may serve as a foundation for subsequent experimental validation and for studies related to neoantigen-based immunotherapies and immunopeptidomics.

Immuno doi: 10.3390/immuno6020020

Authors: Muhammed Zahid Sahin

Nanomaterials (NMs) are increasingly utilized in drug delivery, diagnostic imaging, and therapeutic applications. However, their widespread use raises concerns regarding potential neurotoxicity, particularly for metal and metal oxide nanoparticles. Accumulating evidence indicates that these nanoparticles induce neurotoxicity through interconnected mechanisms, including excessive reactive oxygen species generation, activation of neuroinflammatory pathways, mitochondrial dysfunction, and disruption of blood–brain barrier integrity. These molecular events collectively lead to synaptic impairment, neuronal apoptosis, and progressive cognitive and behavioral deficits, with toxicity severity influenced by dose, exposure duration, and age. Given that in vitro models often fail to capture complex systemic interactions such as nanoparticle biodistribution, blood–brain barrier dynamics, and neuroimmune responses, this review places particular emphasis on in vivo studies to provide a more physiologically relevant understanding of nanoparticle-induced neurotoxicity. Importantly, a growing body of in vivo evidence demonstrates that natural bioactive compounds can mitigate these effects by targeting key pathogenic pathways, including oxidative stress, inflammation, and mitochondrial dysfunction, while preserving neuronal integrity. These findings highlight the therapeutic potential of natural bioactives as protective agents against nanoparticle-induced neurotoxicity and as candidates for broader neuroprotective strategies. This review summarizes the mechanistic basis of metal and metal oxide nanoparticle neurotoxicity and critically evaluates the protective role of natural bioactive compounds, with a focus on evidence derived from animal models.

Immuno doi: 10.3390/immuno6010019

Authors: Carlos M. Ardila Eliana Pineda-Vélez Anny M. Vivares-Builes

Peri-implantitis is a chronic inflammatory condition driven by dysregulated host immune responses, yet clinical risk assessment continues to rely on routinely collected clinical indicators. Clinical prediction models, including machine learning-based and conventional approaches, have been proposed to integrate these indicators for peri-implantitis risk stratification, but their conceptualization of immunopathological risk has not been systematically examined. This systematic review and functional meta-synthesis were conducted according to PRISMA 2020. Six eligible studies were included, comprising 1316 patients and 2438 dental implants. Four studies employed machine learning-based models, and two used conventional clinical prediction approaches. A functional meta-synthesis was performed to interpret how models integrate clinical predictors as surrogate manifestations of immune dysregulation. Additionally, an exploratory random-effects meta-analysis of area under the receiver operating characteristic curve (AUC) values was conducted where applicable. Discriminative performance ranged from moderate to high across studies, with overlapping AUC estimates between modeling paradigms. Despite methodological differences, both machine learning and conventional models converged on shared immunopathological constructs related to inflammatory burden, prior periodontal disease, plaque-related factors, and host systemic conditions. These findings support the clinical utility of immunopathologically informed prediction models for peri-implantitis and highlight the need for future studies incorporating external validation.

Immuno doi: 10.3390/immuno6010018

Authors: Tejas Yuvaraj Suryawanshi Neha Redkar Akanksha Sharma Jyotsna Mishra Sumit Saxena Shobha Shukla

Neuroinflammation is a central hallmark of numerous neurological disorders, including Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, and spinal cord damage. Its persistent and dysregulated nature not only accelerates neuronal loss but also impedes endogenous repair, posing a major challenge for effective therapeutic intervention. Recent advances in nanobiotechnology have opened transformative opportunities to modulate neuroinflammation with unprecedented precision while simultaneously supporting neural regeneration. This review highlights emerging nanomaterial-based strategies including lipid-based, polymeric, inorganic nanoparticles designed to traverse the blood–brain barrier (BBB), deliver anti-inflammatory agents, modulate immune cell behavior, and attenuate glial activation. Extending beyond nanoparticle-based delivery systems, recent advances also emphasize the integration of nanomaterials into biomimetic architectures to provide structural and functional cues for neural repair. We further summarize how these functional nanostructured scaffolds, such as extracellular matrix (ECM) mimetic, nanofibrous and conductive hydrogels, are being leveraged in neural tissue engineering to direct stem cell fate, promote axonal outgrowth, and rebuild damaged neuroarchitectures. Moreover, pharmacokinetics, biodistribution, safety, clinical trials, regulatory considerations and limitations of nanotherapeutics in neurodegenerative diseases are discussed. By outlining the current progress, mechanistic insights, and translational challenges, this review underscores the potential of nanobiotechnology-enabled therapeutics to revolutionize the treatment of neuroinflammatory conditions and advance next-generation neural repair technologies.

Immuno doi: 10.3390/immuno6010017

Authors: Sofia M. Gulova Alina E. Ershova Alexander N. Shumeev Sophia N. Rizatdinova Alexandra V. Pavlova Daria A. Bogdanova Irina V. Astrakhantseva

In the post-pandemic era, monitoring adaptive immunity of the population to emerging SARS-CoV-2 variants remains an important public health priority. To address this need, we developed a test that can simultaneously assess the neutralization ability of three SARS-CoV-2 variants. A panel of lentiviral pseudoviruses, each bearing the S-protein of different SARS-CoV-2 variants (Wuhan-Hu-1, BA.1, and XBB.1.5) and expressing a unique fluorescent protein (Clover, mRhubarb713, or mRuby3) was generated and used to transduce hACE2-overexpressing cells. The percentage of infected target cells for each variant was quantified via flow cytometry. Co-infection led to a minor reduction in the percentage of infected cells compared to mono-infection controls, confirming the robustness of the assay. We then applied the test to the analysis of human sera samples, which were collected in the Sirius Federal Territory (Russian Federation) and revealed the following: (1) sera collected in 2021 neutralized the Wuhan-Hu-1 variant and demonstrated cross-specificity to the BA.1 variant, but not to the XBB.1.5 variant; (2) sera collected after the Omicron emergence point neutralized Wuhan-Hu-1 and BA.1, and possessed a weak ability to neutralize the XBB.1.5. This assay provides a valuable tool for efficient profiling of humoral immunity and monitoring its development in response to ongoing viral diversity.

Immuno doi: 10.3390/immuno6010016

Authors: Grace Alexander Linder Wendt Patrick Ten Eyck Erin Sternhagen Gulsen Ozen Petar Lenert

The primary objective is to determine predictors of pulmonary hypertension (PH) development in patients with centromere antibody (ACA) positive systemic sclerosis (SSc) and to assess survival in patients with and without PH. This was a retrospective cohort study that included both prevalent and incident SSc patients with ACA. Clinical characteristics, mortality and immunomodulatory use were compared between SSc-ACA+ patients with and without PH. Univariable and multivariable logistic regression models, along with a univariable Cox proportional hazards model, were used to assess predictors and survival of PH, respectively. Of 146 SSc-ACA+ patients, 25 (17.1%) developed PH. Patients with PH had more frequent obstructive sleep apnea (36% vs. 12%), heart failure (44% vs. 7.4%), arrhythmias (32% vs. 12%), valvular heart disease (VHD) (32% vs. 8.3%), and chronic kidney disease (36% vs. 12%) than those without PH. In the multivariable logistic regression analysis, VHD was associated with an increased risk of PH development (OR = 7.79), while immunomodulatory use before PH was associated with a reduced risk of PH (OR = 0.34). Patients with PH who received immunomodulatory therapy had a better survival than those with PH without immunomodulatory treatment (p = 0.0008). PH is associated with high mortality in patients with SSc-ACA+. Immunomodulatory use may lower the incidence and mortality of PH in patients with SSc-ACA+ disease. Further randomized studies are needed to confirm this assumption.

Immuno doi: 10.3390/immuno6010015

Authors: Elvis Matini Enas Abouelela Olabisi Ogunbiyi Ali Abdulnabi Suwaidan

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most hard to treat malignancies, characterised by significant immune evasion and resistance to current systemic agents. Despite substantial progress in understanding tumour immunology across other cancer types, PDAC continues to exemplify an immunologically “cold” tumour, where a desmoplastic stroma, inadequate T-cell infiltration, and complex immunosuppressive networks combine to impede effective anti-cancer immunity. This review summarises current knowledge on the mechanisms underlying immune escape in PDAC, including aberrant antigen presentation, stromal–immune crosstalk, recruitment of regulatory T cells and myeloid-derived suppressor cells, and the metabolic and hypoxic constraints imposed by the tumour microenvironment. We also discuss recent advances in preclinical and clinical studies aiming to overcome these barriers, ranging from stromal modulation and targeting immune checkpoints to integrating radiotherapy, chemotherapy, and DNA damage response modulation to enhance immunogenicity. Special emphasis is placed on the emerging concept of therapeutic replication stress and its potential to induce immunogenic cell death and reshape the tumour immune landscape. We outline the mechanistic basis for treatment resistance of PDAC and discuss strategies to convert the malignancy from an immune-resistant to an immune-responsive state.

Immuno doi: 10.3390/immuno6010014

Authors: Alexander Jacob Harbir Singh Poolakkad S. Satheeshkumar Aum Champaneri Rahul K. Das Ravi K. Aalinkeel Supriya D. Mahajan Jessy J. Alexander

The complement system is a central component of innate immunity with established roles in host defense and emerging functions in neurodevelopment, synaptic remodeling, and neuroimmune communication within the central nervous system (CNS). In parallel, advances in nanotechnology have not only enabled targeted strategies for CNS drug delivery but have also revealed that many nanomaterials interact with and activate complement, influencing biodistribution, safety, and inflammatory responses. Opioid use disorder (OUD) is increasingly recognized as a condition associated with chronic neuroimmune dysregulation involving glial activation, altered cytokine signaling, and blood–brain barrier (BBB) disruption. However, direct experimental or clinical measurements of complement activation in OUD remain limited. Current evidence linking complement pathways to opioid exposure is derived largely from indirect observations, including transcriptomic alterations, glial phenotypes, and inflammatory signatures in preclinical and translational models, which collectively suggest, but do not yet definitively establish, complement involvement in opioid-induced neuroimmune signaling. This review synthesizes current knowledge at the intersection of complement biology, nanomedicine, and opioid-associated neuroimmune changes. It distinguishes well-established mechanisms of complement activation by nanomaterials from emerging and inferential evidence linking complement signaling to opioid exposure. This hypothesis-generating framework integrates complement signaling with opioid receptor and TLR4 pathways in glial and endothelial compartments, examining their potential protective and pathological CNS roles while outlining the translational promise and current evidence gaps of complement-aware nanotechnologies for addiction neuroscience.

Immuno doi: 10.3390/immuno6010013

Authors: Jolie F. van der Heiden Anje A. te Velde

Research has shown that diet significantly influences the chance of developing chronic inflammatory diseases including inflammatory bowel disease, cardiovascular disease, obesity, type 2 diabetes and several types of cancer. Dietary components modulate the immune system by either promoting or mitigating inflammatory pathways. One such pathway is the activation of the NLRP3 inflammasome—a multiprotein complex that is involved in the innate immune response. The NLRP3 inflammasome is triggered by various stimuli including ionic flux, mitochondrial dysfunction, lysosomal damage and ROS. Upon activation through a two-signal process, an immune response is initiated that protects the body against pathogens and cellular stress. In a healthy body, this pathway is closely regulated to maintain homeostasis and prevent excessive inflammation that can result in tissue damage or chronic inflammatory diseases. Several components present in a human diet can activate or inhibit the NLRP3 inflammasome. To support a balanced diet, organizations like the WHO have developed dietary recommendations. These promote the consumption of fruits, vegetables, whole grains, lean proteins and healthy fats. These foods contain a variety of nutrients and bioactive compounds, including saturated fatty acids, cholesterol, omega-6 fatty acids and natural sugars, which are pro-inflammatory. At the same time, they also supply anti-inflammatory compounds such as monounsaturated fatty acids, antioxidants and probiotics. While current literature highlights the NLRP3 inflammasome as a critical regulator of inflammation, it lacks detailed insights into how the specific dietary components of a healthy diet influence its modulation. Therefore, this literature review elucidates the various mechanisms through which these dietary compounds modulate the NLRP3 inflammasome. The significance of maintaining a balance between pro- and anti-inflammatory components in the diet is highlighted by its role as a regulator of inflammatory diseases, for example, through mechanisms such as epigenetic pathways.

Immuno doi: 10.3390/immuno6010012

Authors: Uma Maheswari Deshetty Seema Singh Frida L. Martínez-Cuevas Stuti Jain Shilpa Buch Palsamy Periyasamy

Extracellular vesicles (EVs) constitute a heterogeneous group of membrane-derived particles generated through distinct biogenesis pathways, each regulated by precise molecular mechanisms. They carry a diverse array of cargo that reflects the physiological or pathological state of their parent cells. Their classification continues to evolve, as advances in isolation and characterization techniques have revealed novel vesicle subpopulations beyond the traditional categories of microvesicles, and apoptotic bodies, further highlighting the complexity of the EV landscape. Within the central nervous system (CNS), neurons, microglia, astrocytes, oligodendrocytes, and endothelial cells actively release EVs that contribute to intercellular communication. Growing evidence demonstrates that these vesicles play critical roles in neuroinflammation and neurodegeneration by transporting bioactive molecules that influence disease pathways. Their ability to cross the blood–brain barrier allows CNS-derived EVs to be detected in peripheral fluids, making them promising candidates for noninvasive biomarkers. Moreover, EVs are increasingly being explored as therapeutic tools due to their stability, biocompatibility, and capacity to deliver targeted molecular cargo. In this review, we provide a comprehensive overview of EV biogenesis and release mechanisms in CNS cell types, discuss their emerging functions in neuroinflammatory and neurodegenerative disorders, and summarize current advances in EV-based diagnostics and therapeutic approaches, including ongoing clinical trials.

Immuno doi: 10.3390/immuno6010011

Authors: Hyukmin In Kyung Ho Han

Stem-cell differentiation technologies have traditionally relied on recombinant growth factors, cytokines, and morphogens to initiate and guide lineage specification toward clinically relevant cell types. These approaches have enabled substantial progress in regenerative medicine, as exemplified by recent advances in cell-replacement therapies for Parkinson’s disease, type 1 diabetes, and retinal degeneration. However, protein-based ligands and soluble factors are often limited by short half-lives, pleiotropic signaling, condition-dependent effects, and challenges in achieving precise spatial and temporal control in scalable systems. In this review, we survey differentiation strategies driven by administered substances, organizing the field into five material-centric modules: recombinant growth factors, cytokines, morphogens, exogenous ligands, and agonist antibodies. For each module, we summarize mechanistic principles, representative studies, controllable variables, and translational considerations. While growth factors, cytokines, morphogens, and exogenous ligands remain central tools for directing lineage commitment and maturation, recent studies indicate that agonist antibodies offer an additional and distinct means of controlling differentiation outcomes. These antibodies can function as receptor agonists while also imparting tissue-selective effects, enabling lineage specification with coordinated spatial targeting. By focusing on differentiation methods driven by administered molecules and excluding direct physical stimulation or complex 3D constructs, this review provides a framework that is particularly relevant to immunology and translational practice. We highlight agonist antibody-based induction as an emerging strategy that complements established ligand-based approaches and may broaden the design space for clinically applicable stem-cell differentiation.

Immuno doi: 10.3390/immuno6010010

Authors: Sonia Elia Ishaq Taban Kamal Rasheed Niaz Albarzingi

Rheumatoid arthritis (RA) is triggered by dysregulated cytokine networks, but the distributional association of conventional synthetic (csDMARDs) and biologic DMARDs (bDMARDs) with circulating mediators has not been fully described. In this study, we aimed to investigate the treatment-associated modulation of TNF-α, IL-17, IL-13, and soluble CTLA-4 (sCTLA-4) in 64 RA patients (untreated, n = 14; csDMARD, n = 32; bDMARD ± csDMARD, n = 18) and 20 controls. ELISA was used to determine the serum levels, and Kruskal–Wallis tests and false discovery rate correction were used to determine the differences between groups, accompanied by DAS28- and CRP-adjusted quantile regression. Group-level analysis demonstrated that the levels of IL-17 were higher in patients treated with csDMARDs and bDMARDs than in the controls (FDR-adjusted p = 0.0009 and <0.0001, respectively), and the levels of IL-13 were higher in patients treated with bDMARDs than in the controls (p = 0.026). However, quantile regression did not reveal consistent treatment-related associations, suggesting that long-term pathway-specific immune responses and context-dependent regulation may be involved. Smoking independently predicted higher IL-13 at lower quantiles (β = 35.5; p < 0.0001), while TNF-α showed treatment-related increases only at the upper quantile in CRP-adjusted models (β = 323.7; p = 0.049). On the other hand, sCTLA-4 had the largest and most significant treatment-based increase (p < 0.0001), regardless of disease activity, and constant effects across mid-quantiles. Taken together, these findings suggest that sCTLA-4 shows therapy-responsive distributional changes, supporting its potential utility as a biomarker of biological efficacy. In contrast, the observed increases in IL-17 and IL-13 reflect ongoing immune activity and possible environmental influences. Distribution-sensitive biomarker profiling provides a nuanced approach to capturing immune response diversity in RA and may enhance precision in monitoring procedures.

Immuno doi: 10.3390/immuno6010009

Authors: Igor D. Zlotnikov Alexander A. Ezhov Elena V. Kudryashova

The balance of alveolar macrophage (AM) polarization is severely disrupted in chronic inflammatory diseases like bronchiectasis, where a persistent pro-inflammatory (M1) phenotype perpetuates inflammation. To address this, we developed a high-throughput platform using a series of synthetic glycoligands (L1-L5) on a polyethyleneimine (PEI) scaffold. These ligands, which have varying affinities for macrophage lectin-like receptors, were used for phenotypic “fingerprinting” of AM subpopulations from pediatric bronchiectasis patients and a healthy control. Analysis of bronchoalveolar lavage fluid (BALF) revealed a pathogenic, M1-dominant profile (55% M1) in patients, confirming a state of chronic inflammation, which starkly contrasted with the quiescent, M0-dominant profile in the healthy control. We then leveraged this platform for targeted immunomodulation, using a drug-ligand conjugate to steer the dysregulated macrophage population toward a healthy state. The most potent conjugate, Dox-L5, dramatically suppressed the pathogenic M1 population (from 55% to 16%). This M1 suppression was accompanied by a significant shift toward the M2a (tissue-repair) phenotype and the emergence of a quiescent M0-like population, effectively remodeling the AM profile. This work validates a glycan-based platform for both diagnosing and correcting pathological macrophage imbalances. Our targeted approach offers a precise strategy to resolve chronic inflammation in bronchiectasis by suppressing M1 macrophages and promoting a pro-resolving M0/M2 phenotype, thereby restoring lung homeostasis.

Immuno doi: 10.3390/immuno6010008

Authors: Ana Valentina Centeno-Iglesias Celeste Abigail Quille-Juarez Paul Galvez-Murillo Anggie Stefany Revilla-Zeballos Gustavo Alberto Obando-Pereda Luis Alberto Ponce-Soto

Chagas disease, caused by Trypanosoma cruzi, affects a significant proportion of patients who develop digestive and cardiac complications, including megaviscera. This pathogenesis has been associated with autoimmune mechanisms mediated by molecular mimicry. In this study, an in silico evaluation of the potential structural basis of cross-reactivity of β-tubulin 1.9 of T. cruzi and the human β-4A tubulin isoform 3 was conducted. Using bioinformatics tools, homologous regions were identified and potentially immunogenic epitopes were predicted, considering their structural modeling and molecular docking. The proteins shared 87% sequence identity and 95% similarity, with an almost identical structural overlap, RMSD 0.291 Å. Three epitopes, VPFPRLHFF, NDLVSEYQQYQDATI, and GQSGAGNNWAKGHYTEGAELIDS, exhibited high predicted antigenicity, with the 9-mer and 16-mer peptides displaying structurally compatible docking poses within the binding grooves of MHC class I and class II molecules, respectively, while B-cell epitope potential was inferred from sequence-based property predictions. Normal mode analysis, used as an exploratory approach, suggested comparable flexibility profiles for the parasitic- and human-derived peptide–MHC complexes. These findings provide an exploratory structural framework supporting a potential role of β-tubulin epitopes in molecular mimicry processes implicated in the development of chagasic megaviscera.

Immuno doi: 10.3390/immuno6010007

Authors: Tess Cremers Nataliya Miz Alexandra Afanassiev Ling Yang Kevin P. Kotredes Ana M. Gamero

Signal transducer and activator of transcription 2 (STAT2) is a key component of the type I interferon (IFN-I/III) signaling pathway, which is pivotal in host defense against cancer and viral infections and in shaping immune responses. Building on our previously reported conditional Stat2 knockout (KO) mouse, we expand its utility by validating additional tissue-specific models and exploring novel functional contexts. Mice carrying loxP-flanked Stat2 alleles were crossed with CMV-Cre, Cdx2-Cre or CD11c-Cre mice. Deletion of STAT2 was validated by PCR genotyping and western blotting in the relevant tissues. To confirm defective IFN-I signaling with STAT2 deletion, IFN-β stimulation of splenocytes from CMV-Cre Stat2 KO mice showed a lack of induction of canonical IFN-I target genes, confirming functional disruption of the pathway. In vivo, global Stat2 deletion significantly impaired the antitumor efficacy of IFN-β treatment. Similarly, lung fibroblasts isolated from globally deleted Stat2 KO mice showed defective antiviral responses to IFN-β. Tissue-specific Cre models demonstrated selective ablation of STAT2 in target compartments without affecting its expression in non-target tissues. Together, these studies expand our published conditional Stat2 KO findings and highlight the value of this model as a versatile platform for dissecting STAT2-dependent signaling pathways in a tissue- and disease-specific manner.

Immuno doi: 10.3390/immuno6010006

Authors: Fatin Najiah Mohd Idrus Hayat Asaad Hameed Al-Ali Zahidah Nasuha Mohd Yasin Maryam Azlan Rapeah Suppian See Too Wei Cun Hoe Chee Hock Nurul Shuhadah Ahmad Zurkurnai Yusof Wan Yus Haniff Wan Isa Akbar Ali Mohamed Ali Yvonne-Tee Get Bee

Efferocytosis, the process by which macrophages clear apoptotic cells, plays a vital role in maintaining immune homeostasis. This study explores the influence of inflammatory cytokines—tumor necrosis factor-alpha (TNF-α) and transforming growth factor-beta (TGF-β)—on efferocytosis dysregulation in coronary artery disease (CAD). Peripheral blood samples were collected from 27 non-obstructive and 29 obstructive CAD patients to isolate monocytes, which were then differentiated into M1 and M2 macrophages using specific cytokine stimuli. These macrophages were transfected with TNF-α and TGF-β siRNA to assess cytokine impact on efferocytosis. Expression levels of the efferocytosis receptor MERTK and its regulatory protease ADAM17 were quantified via qPCR. Statistical analysis revealed significantly higher MERTK expression in M2 macrophages compared to M1 (p = 0.002). Notably, TNF-α silencing enhanced efferocytosis in M2 macrophages, with increased clearance of early apoptotic bodies in non-obstructive CAD and late apoptotic bodies in obstructive CAD (both p < 0.001). These findings suggest that macrophage phenotype, apoptotic stage, and cytokine environment influence efferocytosis efficiency and may involve pathways beyond MERTK-ADAM17. They offer preliminary mechanistic insights into cytokine-mediated modulation of efferocytosis in CAD. Further in vivo studies are needed to confirm these observations and evaluate their relevance for future therapeutic strategies.

Immuno doi: 10.3390/immuno6010005

Authors: Ahmed M. Tabl Mohamed E. Ebeid Yasser B. M. Ali Khaled A. Elawdan Mai Alalem Ahood A. Al-Eidan Nedaa Alalem Ahmed S. Mansour Ahmed M. Awad Eman A. El-Madawy Shymaa A. Elbuckley Rofaida Refaai Amany M. Elshamy Hany Khalil

Colorectal tumors consist of diverse cell populations, including cancer cells and immune cells. Sorafenib (Nexavar), an oral multikinase inhibitor, targets tumor growth and angiogenesis while inducing apoptosis. However, its clinical use is hindered by poor solubility, rapid metabolism, and low bioavailability. This study explores a nanotechnology-based approach to enhance Sorafenib’s efficacy against colon cancer. Nexavar was encapsulated into nanoparticles using an oil phase and Span 80 as a stabilizer to produce sub-100 nm droplets. The resulting Nano-Nexavar was evaluated for cytotoxicity on Caco-2 colorectal cancer cells and compared with free Nexavar on both Caco-2 and normal NCM-460 colon cells. Nano-Nexavar significantly reduced cancer cell viability at lower concentrations, with no observed toxicity to normal cells. Both formulations induced lactate dehydrogenase release and cell reduction at 2.5 µM, but Nano-Nexavar triggered nearly 60% apoptosis in Caco-2 cells. It inhibited Raf-1, NFκB, and ERK signaling, and reduced epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) levels over time. Notably, unlike Nexavar, the Nano-Nexavar suppressed aspartate β-hydroxylase (ASPH) and enhanced mitochondrial-mediated apoptosis by increasing Bax expression, mitochondrial accumulation, and mtDNA levels indicated by immunofluorescence, immunoblotting, flow cytometry, and qRT-PCR. These data demonstrate that Nano-Nexavar potentiates Sorafenib’s anticancer activity by targeting ASPH, thereby amplifying mitochondrial signaling–induced cell death.

Immuno doi: 10.3390/immuno6010004

Authors: Zaida Araujo Jacobus Henri de Waard Mercedes Fernández-Mestre Douglas Silva Carmen Judith Serrano Luis Adrián De Jesús-González Juan Ernesto Lopez-Ramos Bruno Rivas-Santiago

Tuberculosis (TB) has various clinical presentations; pulmonary TB (PTB) affects only the lungs, whereas extrapulmonary TB involves other organs, including pleural TB (PLTB). Immunological studies of patients with extrapulmonary TB primarily focus on the cellular Th1 response, which produces key cytokines, including IFN-γ, TNF, IL-12, and IL-6. TNF and IL-6 play functional roles in host resistance to Mycobacterium tuberculosis (Mtb) infection. Findings suggest that TNF facilitates macrophage containment of Mtb, whereas IL-6 increases macrophage apoptosis induced by Mtb. Studies of the human genome have identified single-nucleotide polymorphisms (SNPs) in genes encoding cytokines associated with TB susceptibility. This study aimed to assess the potential of the IL6-174G/C (rs1800795), TNF-308G/A (rs1800629), and TNF-238G/A (rs361525) SNPs as genetic biomarkers of susceptibility to PLTB in the Venezuelan mestizo population. A total of 269 individuals were included: 69 patients with PLTB and 200 healthy individuals. The IL6-174G/C, TNF-308G/A, and TNF-238G/A polymorphisms were determined by sequence-specific primer polymerase chain reaction (SSP-PCR). Results showed significantly higher frequencies of the G/C, G/A, and G/A genotypes in patients with PLTB (94.0%, 94.2%, and 83.3%) than in controls (40.0%, 19.0%, and 13.4%) for the IL6-174G/C, TNF-308G/A, and TNF-238G/A polymorphisms, respectively. Logistic regression analysis showed significant associations between the G/C, G/A, and G/A genotypes and susceptibility to PLTB. The IL6-174G/C, TNF-308G/A, and TNF-238G/A gene polymorphisms may serve as genetic biomarkers of susceptibility to PLTB in the Venezuelan mestizo population.

Immuno doi: 10.3390/immuno6010003

Authors: Dimitar Parvanov Dimitar Metodiev Rumiana Ganeva Margarita Ruseva Maria Handzhiyska Jinahn Safir Lachezar Jelezarsky Nina Vidolova Georgi Stamenov Savina Hadjidekova

Successful implantation requires a finely regulated endometrial microenvironment during the window of implantation. Chronic endometritis, defined by plasma cell infiltration, and stromal senescence, indicated by p16 expression, represent separate but potentially interacting mechanisms associated with impaired endometrial receptivity. The relationship between these processes remains poorly understood. We aim to examine whether stromal senescence is associated with plasma cell density and clustering in the human endometrium during the implantation window. Forty mid-luteal (LH+7) endometrial biopsies were retrospectively analyzed and stratified into low-senescence (<0.5% stromal p16+ cells, n = 20) and high-senescence (>3.5%, n = 20) groups. Plasma cells were identified by immunohistochemistry for MUM1 and CD138 and quantified using HALO® software (version 3.4). Group comparisons were performed using Student’s t-test and chi-squared analysis. CD138+ plasma cells were significantly more abundant in high-senescence endometria than in low-senescence controls (0.065 ± 0.10 vs. 0.014 ± 0.027 cells/mm2, p = 0.02). Only MUM1+ cells formed stromal clusters, which were more frequent in high-senescence samples (67% vs. 31%, p = 0.05). High endometrial stromal senescence during the implantation window is associated with increased plasma cell infiltration and clustering. This interplay may contribute to chronic endometritis and impaired receptivity, providing new insights into potential diagnostic and therapeutic strategies for reproductive failure.

Immuno doi: 10.3390/immuno6010002

Authors: Elizabeth Doar Jessica Kishiyama Zolton J. Bair Chase Beathard

Hericium erinaceus is a medicinal mushroom valued in the wellness industry for its neuroprotective, immunomodulatory, and antioxidant activities. While many extracts and bioactive compounds from both mycelium and fruit bodies have been characterized, the mechanisms driving their effects are not fully understood. Here, the transcriptomic and protein-level effects of H. erinaceus mycelium (HDLM) in human peripheral blood mononuclear cells (PBMCs) were investigated, along with antioxidant and iron chelating activity. A commercially available H. erinaceus fruit body extract (FBE) claiming high β-glucan content was included in a subset of assays to compare immune-related outcomes between mycelial and fruit body constituents. HDLM activated a wide array of immune- and oxidative stress-related transcripts and pathways, exhibited significant antioxidant activity, and consistently reduced IL-1β, TNF-α, and IL-8 during LPS challenge while maintaining low basal cytokine expression, indicating targeted immunomodulatory activity. FBE almost doubled production of IL-1β when challenged by LPS, whereas HDLM significantly decreased production of this stress mediator. HDLM also demonstrated augmented iron chelating ability when compared to FBE. Depending on tissue source and preparation methods, different H. erinaceus materials may either potentiate or quench stress responses, highlighting the need for further bioactivity and safety comparisons across H. erinaceus supplements, particularly with respect to cytokine regulation under conditions of immune challenge.

Immuno doi: 10.3390/immuno6010001

Authors: Jenny Valentina Garmendia Isaac Blanca Juan Bautista De Sanctis

Unexplained infertility and idiopathic recurrent pregnancy loss (RPL) have a prevalence of 1–5% of women of reproductive age in different populations. There are a few reports comparing the circulating immune cell populations and subpopulations in these medical entities in admixed populations. The study aimed to assess the different leukocyte, mononuclear cell populations, and T lymphocyte subpopulations and HLADR expression, as a marker of activation, in an admixed group of Venezuelan women: 80 controls, 73 women with RPL (53 primary, 20 secondary), and 26 infertile (20 primary, six secondary). Endometriosis was clinically ruled out in all patients and controls. Total leukocytes were 10–12% higher (p < 0.0001) in the infertile group, while neutrophils were 11% in the infertility group (p < 0.0001). In contrast, lymphocytes, CD3CD4 cells, NK cells, and HLADR+ cells were elevated (10–15, 18–22, 50–60, and 700–800% increase, respectively) in all patient groups. Changes in B cell numbers and monocyte counts were also observed. HLADR expression was significantly increased (p < 0.0001) in T cells, CD56+ cells, and monocytes of all patients. In infertile patients, a correlation was recorded between HLADR and T memory cells. Marked differences in peripheral blood leukocytes, NK cells, monocytes, T-cell populations, and HLADR suggest a proinflammatory effect. HLADR can be used as a simple biomarker to monitor pharmacological treatment in these patients.

Immuno doi: 10.3390/immuno5040062

Authors: Mohammad Shahid Iqbal Ahmad F. Arbaeen M. A. Bendary Hasan H. Qadi Aisha Tabassum Othman M. Fallatah Sami Melebari Nadeem Ikram Mohammed Parvez Kamal H. Alzabeedi

T cells and B cells are central components of the adaptive immune system, orchestrating immune responses through a complex network of interactions. This review explores the dynamic interplay between T and B cells, focusing on their development, activation, and functional coordination in immune defense. T cells provide essential help to B cells through cytokine signaling and direct cell–cell interactions, facilitating antibody production and affinity maturation in germinal centers. Conversely, B cells contribute to antigen presentation and cytokine modulation, influencing T cell differentiation and function. The regulation of these interactions is critical for maintaining immune homeostasis, preventing autoimmunity, and enhancing vaccine efficacy. Dysregulation of T-B cell crosstalk is implicated in various immune disorders, including autoimmune diseases and immunodeficiencies. Recent advances in immunotherapy have targeted these pathways to modulate immune responses in conditions such as cancer, infections, and inflammatory diseases. This review synthesizes current knowledge on T and B cell physiology, highlighting emerging research on their cooperative mechanisms.

Immuno doi: 10.3390/immuno5040061

Authors: Domenico De Falco Diego Misceo Giuseppe Carretta Gioele Gioco Carlo Lajolo Massimo Petruzzi

Angioedema (AE) is a heterogeneous condition characterized by acute, localized, non-pitting edema of the skin, mucosa, and submucosal tissues, with potentially life-threatening airway involvement. This comprehensive review aims to provide an updated overview of the different AE subtypes, their pathogenesis, clinical presentation, diagnostic criteria, therapeutic strategies, and dental implications. A literature search of PubMed, MEDLINE, and Google Scholar was performed for articles published between 1950 and 2025, focusing on both bradykinin- and histamine-mediated forms. The findings highlight the importance of distinguishing histaminergic AE, which typically responds to antihistamines, corticosteroids, and epinephrine, from bradykinin-mediated AE, which requires targeted therapies such as C1 esterase inhibitor (C1-INH), icatibant, or kallikrein inhibitors. Subtypes including hereditary, acquired, and drug-induced AE are reviewed, with emphasis on diagnostic markers (C4, C1-INH, C1q) and recent genetic insights in HAE-nC1INH. In dental and surgical settings, invasive procedures may act as triggers, making prophylaxis with plasma-derived C1-INH and stress management strategies essential. In conclusion, accurate subtype recognition is crucial to guide therapy and perioperative care, and further research is needed to refine diagnostic algorithms and preventive strategies.

Immuno doi: 10.3390/immuno5040060

Authors: Krista Yasuda Rebecca Jean Ryznar

Autoimmune disease (AD) is a breakdown of self-tolerance by the immune system and has a variety of clinical manifestations and complications across all organ systems. One of the targets for treatment of AD aims at reducing inflammation and upregulating factors that eliminate autoreactive cells. Intermittent fasting (IF) has recently gained popularity as a dietary intervention for weight management, but has also been found to interact and positively interfere with pathways involved in the pathophysiology of AD. Methods include searching in the PubMed and Google Scholar databases for reviews and clinical trials studying any relationships between AD and IF. The search results have identified a variety of anti-inflammatory effects IF has on the immune system that can potentially reduce AD severity and several trials specifically studying IF’s effects on type I diabetes (T1D), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and multiple sclerosis (MS). Based on the findings, IF has potential anti-inflammatory effects that could assist with decreasing AD severity. Future directions include studies to further determine safety and efficacy of IF with AD, broader investigations to include IF’s impact on a wide variety of ADs, an ideal time frame of how long patients should remain on IF, and any potential interactions IF may have on current drug therapies used to treat AD. This review also aims to encourage more human studies of IF and its application to AD given that many of these results are largely from in vitro, cellular and molecular, and animal studies.

Immuno doi: 10.3390/immuno5040059

Authors: Marwa Omar Ghada Fathy Samira Mohammed Asmaa El-taib

The exact role of nitric oxide (NO) in the complex interplay between the host and Trichinella spiralis (T. spiralis) parasite remains uncovered. While much has been revealed about the role of the inducible isoenzyme (iNOS) in different parasitic infections, research is slowly progressing toward understanding the neuronal enzyme (nNOS)-derived impacts on trichinosis. This study aims to clarify the dual nature of (NO) during the enteral phase of experimental trichinosis by examining the participation of both iNOS and nNOS in T. spiralis-infected mice. The experimental design included 48 male Swiss albino mice divided into six groups: (G1) negative control, (G2) infected control, (G3) infected–Albendazole-treated, (G4) infected-infected–L-arginine-treated, (G5) infected–Aminoguanidine-treated, and (G6) infected–7-Nitroindazole-treated. On the seventh day post-infection, the study groups underwent parasitological (adult worm count), histopathological, immunohistochemical, and biochemical assessments. Our results showed that (nNOS) predominance during the enteral phase of trichinosis enhanced parasitic clearance. Conversely, NO produced by iNOS was not essential for worm expulsion but contributed to T. spiralis-mediated enteropathy. Nitric oxide seems to play a puzzling role in T. spiralis infection. While (iNOS) is known for eliminating numerous infections, this is the first example we are aware of where the activity of the neuronal isoform (nNOS) is required in trichinosis.

Immuno doi: 10.3390/immuno5040057

Authors: Tripti Singh Shivani Sharma Animesh Tripathi Sunil Kumar Anchal Singh

Filarial parasites are long-lived organisms that cause extreme morbidity due to pathological manifestations, including lymphedema, hydrocele, and elephantiasis. Understanding the hosts’ immune responses to filarial parasites is crucial to developing new and effective anti-filarial treatments. The review thoroughly examines and summarises immunological modulation, evasion strategies, and filarial–host immune interactions to provide an updated knowledge of the immune evasion manoeuvres used by filarial parasites. An extensive literature search was conducted using databases such as PubMed, Google Scholar, ScienceDirect, Web of Science, and Scopus to identify articles published mostly between 2000 and 2025 that focus on the crucial molecular, cellular, and immunomodulatory strategies of filarial parasites. The immune evasion mechanisms include the modulation of effector T cells, induction of apoptosis in immune cells, the release of immunomodulatory proteins, and the induction of regulatory immune cell populations, thereby ensuring the mutual survival of both the parasite and the host. An antigen-specific T helper 2 (Th2) response and an increase in Interleukin-10 (IL-10) producing CD4+ T cells, along with a suppressed T helper 1 (Th1) response, are the key immunological characteristics of filarial pathogenesis. This antigen-specific T-cell hyporesponsiveness seems necessary for keeping the long-term infection going, which often involves large parasite densities. This review summarises filarial parasites’ mechanisms and strategies in regulating host immune responses and will facilitate future studies on the filarial pathogenesis, leading to the development of novel anti-filarial therapeutics.

Immuno doi: 10.3390/immuno5040058

Authors: Wen-Jing Yu Ying Wu Wen-Bing Duan Qi Chen Xu-Ying Pei Jin-Song Jia Jing Wang Xiao-Lu Zhu Xiao-Su Zhao Xiao-Jun Huang Hao Jiang

The clinical features and outcomes of adult acute leukemia (AL)-associated hemophagocytic lymphohistiocytosis (AL-HLH) remain insufficiently characterized. We retrospectively analyzed 45 adult patients diagnosed with AL-HLH between December 2019 and June 2023. Among 746 AL patients, 45 developed HLH, with 40 developing acute myeloid leukemia (AML), 4 developing acute lymphoblastic leukemia (ALL), and 1 developing mixed-phenotype acute leukemia (MPAL). According to the ELN 2022 criteria, 16 (35.6%) had favorable, 3 (6.7%) had interediate, and 26 (57.7%) had poor risk. At the time of HLH onset, seven (15.6%) patients were in composite complete remission (CCR), and 38 (84.4%) were in non-CCR states; 25 (55.6%) patients were newly diagnosed before induction chemotherapy. The HLH-94/04-based regimens (etoposide and dexamethasone) with or without ruxolitinib achieved an ORR (overall remission rate) of 82.2% and a CR rate of 66.7%. After anti-leukemic therapy, 60% (27/45) of patients achieved CCR for leukemia (including patients in CCR at HLH onset and those achieving CCR after treatment). Hematopoietic stem cell transplantation (HSCT) independently predicted sustained remission. The estimated overall rates at 6 and 12 months after HLH diagnosis were 73.1% and 59.2%, respectively. Multivariate Cox analysis identified failure to achieve CCR for leukemia as the only independent adverse prognostic factor. AL-HLH is an uncommon but severe complication that predominantly occurs in AML patients with poor-risk cytogenetics or active disease. Early recognition, effective HLH control, and achievement of CCR in AL are crucial for improving patient prognosis.

Immuno doi: 10.3390/immuno5040056

Authors: Asmaa K. K. AbdelMaogood Marwa G. Tawfik Sally Khattab Heba A. Attea Hidi A. A. Abdellatif Nora Hosny Aya Mohamed Askar

Background: Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease in which cytotoxic T cells contribute to tissue damage through dysregulated effector pathways. CD107a (LAMP-1) serves as a functional marker of CD8+ T-cell degranulation and may reflect disease-related alterations in cytotoxicity. Objective: To investigate the expression of CD107a on cytotoxic T cells in SLE patients and evaluate its relationship with disease activity and immunological features. Methods: Demographic, hematological, and immunological profiles of SLE patients and controls were compared. Flow cytometry was used to evaluate CD3+, CD3+CD8+, CD4+, double-negative T cells, and CD107a+CD8+ subsets. Correlations with disease activity and diagnostic performance were assessed. Results: SLE patients showed anemia, thrombocytopenia, and lymphopenia compared with controls. Immunophenotyping revealed significantly elevated CD3+CD8+, CD107a+CD8+ T cells in SLE, and reduced CD4+ counts. While CD107a+CD8+ levels were strongly elevated, they did not correlate with disease activity scores, suggesting persistent upregulation of CD107a expression independent of clinical severity. ROC curve analysis indicated that CD3+ and CD3+CD8+ subsets had diagnostic utility, while double-negative T cells showed additional value. Conclusion: SLE is associated with increased CD107a+CD8+ T cells, reflecting heightened basal expression of this degranulation marker regardless of disease activity level. These findings underscore the role of altered cytotoxic T-cell function in SLE immunopathogenesis and support CD107a as a potential biomarker of immune dysregulation.

Immuno doi: 10.3390/immuno5040055

Authors: Jenny Valentina Garmendia Isaac Blanca Juan Bautista De Sanctis

Killer-cell immunoglobulin-like receptors (KIRs) play a crucial role in the cytotoxic activity of natural killer (NK) cells, encompassing both inhibitory and activating types. A higher ratio of cytotoxic to inhibitory receptors may harm successful pregnancies by disrupting the uterine environment. Ongoing debates surround the impact of KIR gene variations on recurrent pregnancy loss (RPL) and infertility across populations. This study aimed to explore KIR gene polymorphisms in RPL and infertility among the Venezuelan admixed population. The Venezuelan population exhibits a genetic mix of Caucasian, African, and local Amerindian ancestry, distinguishing it from other Latin American admixed populations. This study included 100 controls and 86 patients: 73 women with idiopathic RPL (53 primary and 20 secondary) and 13 infertile patients (4 primary and 9 secondary). The frequency of activating receptors KIR2DS2 and KIR2DS3 was significantly lower (p < 0.05) in the whole patient group compared to controls. However, when analyzing the haplotypes and genotypes, the significance between patients and controls was lost. When comparing RPL and infertile patients, KIR2DS2, KIR2DL3, 2DL5, and 3DL1 were significantly less frequent in infertile women. In infertile women, KIR2DS3 frequency was increased compared to controls and RPL. The results suggest that the frequency of inhibitory receptors may differentiate patients with RPL and infertility. Further studies should ascertain the expression and function of KIRs in uterine NK cells in patients with RPL and infertility.

Immuno doi: 10.3390/immuno5040054

Authors: Rumiana Ganeva Dimitar Parvanov Margarita Ruseva Maria Handzhiyska Jinahn Safir Lachezar Jelezarsky Teodora Tihomirova Dimitar Metodiev Georgi Stamenov Savina Hadjidekova

Nearly 10% of IVF patients experience repeated implantation failure (RIF). Although several meta-analyses report improved outcomes following peripheral blood mononuclear cell (PBMC) administration, the uterine mechanisms remain poorly understood. We first analyzed PBMC composition and cytokine secretion in a preliminary cohort (n = 18), followed by endometrial immune profiling in a larger cohort (n = 70) before and after PBMC treatment. Embryo transfer was performed in 41 women, enabling the assessment of associations between immune profiles and implantation success. Successful implantation occurred in 16 of 41 embryo transfers (39%). PBMCs were predominantly composed of lymphocytes (60.7%), with T helper cells as the predominant T cell subset (Th/cytT ratio 1.44). Cytokine assays confirmed secretion of TNF-α, IL-6, IL-4, and IL-10. C-reactive protein levels remained below the threshold for systemic inflammation and were unaffected by PBMC administration. In the full cohort, PBMC infusion significantly enriched stromal macrophages and T helper cells, reflected by higher Th/T, Th/MΦ, and Th/cytotoxic T cell ratios and a reduced cytotoxic T/T cell ratio (all p ≤ 0.001). Importantly, women with successful implantation exhibited a significantly higher macrophage/T cell ratio (1.15 vs. 0.74; p = 0.024). These findings suggest that PBMC administration reshapes the endometrial immune landscape and that the macrophage/T cell ratio may serve as a promising biomarker of treatment efficacy.

Immuno doi: 10.3390/immuno5040053

Authors: Sana Amreen Fakeha Masood Glenda Rosas Zuniga Saloni Parkar Yossef Alnasser

Celiac disease (CD) is a chronic autoimmune condition traditionally recognized for its gastrointestinal symptoms. However, growing evidence indicates that CD can also affect social and emotional health, particularly among children. This narrative review explores how the autoimmunity of CD may contribute to social–emotional dysregulation through mechanisms such as neuroinflammation, nutrient deficiencies, and disruption of the gut–brain axis. It summarizes the current literature on anxiety, attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and autism spectrum disorder (ASD), highlighting how immune dysregulation may influence children’s social–emotional wellbeing. Delayed diagnosis, poor dietary adherence, and ongoing inflammation were recognized among children with social–emotional dysregulation. While digestive problems are commonly recognized and treated, social–emotional dysregulation among children with CD is frequently overlooked. However, a gluten-free diet without a confirmed diagnosis of CD is not sufficient to improve social–emotional outcomes. Children presenting with social–emotional dysregulation and clinical features suggestive of CD should be screened using standard serology and, when indicated, biopsy. Starting a gluten-free diet (GFD) without a confirmed diagnosis is not recommended. While mechanistic pathways are described, most evidence remains observational and clinically descriptive, underscoring the need for longitudinal and experimental studies to understand the intersectionality of CD with social–emotional dysregulation.

Immuno doi: 10.3390/immuno5040052

Authors: Jeffrey Fan Yang Ha

Micro- and nanoplastics (MNPs) are emerging environmental immunotoxins with widespread human exposure through ingestion, inhalation, and dermal contact. Detected in the placenta, lungs, blood, bone marrow, and brain, MNPs accumulate in immune organs where they disrupt innate and adaptive cell functions. This review aims to provide a comprehensive summary of the current knowledge on how MNPs affect the immune system at the cellular and molecular levels. Experimental evidence shows that MNPs impair macrophage phagocytosis, skew dendritic cell maturation, trigger neutrophil extracellular traps, and alter T and B cell responses. Mechanistically, these effects are driven by oxidative stress, mitochondrial dysfunction, and activation of key inflammatory signaling pathways, including NF-κB, MAPK, and NLRP3 inflammasome, leading to apoptosis, pyroptosis, and chronic low-grade inflammation. Furthermore, MNP-induced disruption of epithelial barriers and gut microbiota composition undermines immune tolerance and contributes to the pathogenesis of autoimmune conditions. Preclinical models provide evidence linking MNP exposure to exacerbation of diseases such as systemic lupus erythematosus, inflammatory bowel disease, and rheumatoid arthritis. However, human epidemiological data remain limited, highlighting the urgent need for standardized exposure protocols, advanced omics technologies, and longitudinal cohort studies are urgently needed to establish causal links and inform public health strategies.

Immuno doi: 10.3390/immuno5040051

Authors: Margarita Ruseva Dimitar Parvanov Rumiana Ganeva Maria Handzhiyska Jinahn Safir Dimitar Metodiev Georgi Stamenov Savina Hadjidekova

Embryo implantation requires a finely tuned immune balance at the maternal–fetal interface. Interferon tau (IFN-τ), a key immunomodulator in ruminant implantation, may have therapeutic potential in human reproduction. This study investigated its effects on peripheral blood mononuclear cells (PBMCs) in vitro and the subsequent impact on endometrial immune composition following intrauterine administration of these cells. The work was conducted in two stages. First, in vitro assays were performed with PBMCs from 20 patients with recurrent implantation failure (RIF) cultured with or without IFN-τ for 24 h. Cytokines (IL-10, IL-4, TNF-α, IL-6) were measured by ELISA, and T cell subsets (Th, cytT, Th1, Th2, Th9, Tfh, Th17, Treg) were analyzed by flow cytometry. IFN-τ increased IL-4 and reduced TNF-α and IL-6, indicating a Th2 profile shift. T-cell analysis revealed fewer cytT, Th1, Th9, and Th17 cells, more Th2 cells, and improved Th/Tk, Th1/Th2, and Th17/Treg ratios after IFN-τ. A second clinical study included 55 RIF patients who received intrauterine IFN-τ-modulated PBMCs. Post-treatment endometrial biopsies revealed more helper T cells and macrophages, with higher Th/total T, Th/cytT, and Th/macrophage ratios, suggesting a tolerogenic environment. Overall, IFN-τ modulates PBMCs in vitro and promotes a favorable endometrial immune profile in vivo, highlighting its potential as an immunotherapy in assisted reproduction.

Immuno doi: 10.3390/immuno5040050

Authors: Rositsa Mihaylova Viktoria Elincheva Reneta Gevrenova Dimitrina Zheleva-Dimitrova Georgi Momekov Rumyana Simeonova

The inflammatory and metabolic complexity of colitis necessitates therapies that act on multiple immune pathways. Using serum proteomic profiling, the present study evaluated the systemic immunomodulatory profile of Epilobium angustifolium lyophilized methanol-aqueous extract rich in oenothein B (EAE) in a dextran sulfate sodium (DSS)-induced mouse model of ulcerative colitis in a comparative manner to dexamethasone (DXM). DSS exposure triggered robust inflammatory activation, evidenced by elevated chemokines (CXCL9, CXCL10, CCL11), proinflammatory cytokines (IL-1α, IL-12, PAI-1, RAGE) and metabolic stress mediators (leptin, resistin, FGF-21). Treatment with EAE significantly attenuated this inflammatory profile, notably reducing Th2-skewed chemokines and eosinophil recruitment. In contrast to DXM, EAE uniquely normalized pro-thrombotic and tissue-remodeling markers, including PAI-1 and RAGE, both implicated in intestinal barrier dysfunction and chronic inflammation. Furthermore, EAE demonstrated superior modulation of inflammation-associated growth factors (IGFBP-5, HGF, Flt3L) and adipokines (leptin, resistin), indicating a broader therapeutic scope that includes metabolic dysfunctions. Collectively, our data reveal that EAE exerts a distinct immunoregulatory profile, modulating both innate and adaptive immune pathways while simultaneously addressing metabolic pathologies. These multifaceted actions underscore its promise as a phytotherapeutic candidate for the management of ulcerative colitis and other inflammatory conditions, with potential advantages over conventional steroid treatment.

Immuno doi: 10.3390/immuno5040049

Authors: José Lourenço Reis Catarina Martins Miguel Ângelo-Dias Natacha Nurdine Rosa Luís Miguel Borrego Jorge Lima

Background: Endometriosis, believed by many to be rooted in immunology, is a chronic disease. Upregulation of programmed cell death protein 1 (PD-1) in immune cells may compromise their defensive function, a mechanism demonstrated in the context of cancer spread. This study aims to explore the potential involvement of PD-1 in the pathophysiology and progression of endometriosis. A total of 62 patients who underwent laparoscopic surgery were analyzed, with 47 diagnosed with endometriosis and 15 serving as controls. We collected peritoneal fluid and peripheral blood samples during surgery and examined them using flow cytometry. Using a panel of monoclonal antibodies, the samples were stained and the expression of PD-1 in immune cells was evaluated. Results: We observed a statistically significant rise in the percentage of the CD56+ CD16+ NK cell subset expressing PD-1 within the peritoneal fluid of endometriosis patients compared to the control group (p = 0.021). Similarly, we found that PD-1 expression on immune cells significantly differed based on factors such as body mass index and smoking habits. Moreover, peritoneal subsets of PD-1+ T and NK cells showed an increase in patients presenting symptomatic endometriosis and those with more widespread disease. Conclusions: Our evaluation of the inhibitory PD-1 receptor has strengthened the potential connection between immune escape mechanisms often seen in cancer cells and those in endometriotic cells. This concept could pave the way for future research in the field of immunomodulation and endometriosis.

Immuno doi: 10.3390/immuno5040048

Authors: Michael J. Janes Aidan A. Schmidt Garret A. Krieg Amitoj S. Chouhan Mark R. Wakefield Yujiang Fang

Lung cancer is the most common cause of death due to cancer in the world, and non-small cell lung cancer (NSCLC) is the most common form of lung cancer, representing approximately 84% of all cases. Due to its frequency and mortality, the amount of research on this subject has been greatly increased and new techniques to improve health outcomes have been established. While surgery remains the gold standard of treatment, immunotherapy used alone or in conjunction with surgery shows promising results. This review aims to give an overview of current and new surgical and immunotherapy methods used for the treatment of NSCLC, as well as ways in which they can be combined and the clinical outcomes for patients with each treatment modality. Additionally, it will seek to highlight any gaps in current knowledge of treatment and propose further studies to improve the efficacy of NSCLC treatments.

Immuno doi: 10.3390/immuno5040047

Authors: Hassan O. J. Morad Larissa Garcia-Pinto Georgia Clayton Foad Davoodbeglou Arturo Monzon Peter A. McNaughton

Neutrophils are an essential protective component of the innate immune system. However, in severe bacterial infections, neutrophils are known to mis-localise from the primary site of infection to other organs, where excessive release of cytokines, chemokines, and neutrophil extracellular traps (NETs) can induce organ damage and death. In this study, we use an animal model of bacterial infection originating in the peritoneum to show that hydrogen peroxide (H2O2, a potent neutrophil chemoattractant) is initially released in high concentrations both in the peritoneum and in multiple ‘off-target’ organs (lungs, liver and kidneys). The initial high H2O2 release inhibits neutrophil chemotaxis, but after 24 h concentrations of H2O2 reduce and can promote neutrophil migration to organs, where they release pro-inflammatory cytokines and chemokines along with NETs. The antimalarial compound artesunate potently inhibits neutrophil migration to off-target organs. It also abolishes cytokine, chemokine, and NET production, suggesting that artesunate may be a valuable novel therapy for preventing off-target organ inflammation associated with severe bacterial infections. Finally, the potency of H2O2 as a chemoattractant is shown by in vitro experiments in which, faced with competing gradients of H2O2 and other chemoattractants, neutrophils preferentially migrate towards H2O2.

Immuno doi: 10.3390/immuno5040046

Authors: Kawaljit Kaur

Immune cells like neutrophils, monocytes/macrophages, and lymphocytes play key roles in the development, progression, and resolution of deep vein thrombosis (DVT) by contributing to inflammation, coagulation, and fibrinolysis. IFN-γ, a cytokine mainly secreted by natural killer (NK) and T cells, is a critical factor in DVT pathogenesis. It links immune responses to coagulation activation by promoting endothelial activation, leukocyte recruitment, cytokine release, and coagulation imbalance. Its strong pro-inflammatory and prothrombotic effects make IFN-γ a promising target for DVT treatment beyond standard anticoagulants. Exploring ways to block IFN-γ signaling or its downstream effects could open doors to novel therapies for DVT, aiding in resolution and preventing post-thrombotic complications. This review delves into DVT pathophysiology, diagnostics, and management, emphasizing the importance of targeting immune cells and IFN-γ to advance treatment options.

Immuno doi: 10.3390/immuno5040045

Authors: Dwaipayan Saha Preyangsee Dutta Abhijit Chakraborty

Cardiomyopathies affect over 3 million individuals globally, with conventional treatments exhibiting up to 60% resistance and 25% 30-day readmission rates. This review synthesizes the current evidence on the role of neuro-immune interactions in the pathogenesis of cardiomyopathy and evaluates emerging therapies targeting this axis. We systematically examined clinical trials and mechanistic and multi-omics data across cardiomyopathy phenotypes, focusing on autonomic-immune dysregulation. Sympathetic overactivation, present in approximately 85% of patients, correlates with elevated pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) and contributes significantly to therapeutic non-response. Concurrent parasympathetic withdrawal impairs cholinergic anti-inflammatory pathways, as reflected by reduced heart rate variability and baroreflex sensitivity. At the molecular level, shared mechanisms include inflammasome activation, neuroimmune synaptic signaling, and neurogenic inflammation. Emerging therapies targeting this axis are promising. Vagus nerve stimulation, as demonstrated in the INOVATE-HF trial, improves functional outcomes, whereas IL-1β antagonists reduce cardiovascular events by 15–20% in the context of inflammatory diseases. Bioelectronic interventions, such as transcutaneous vagal nerve stimulation and baroreflex activation therapy, offer noninvasive dual-modulatory strategies that address both neural and immune pathways, positioning the neuroimmune axis as a central driver of cardiomyopathy, regardless of etiology. The integration of genetic and metabolomic profiling may enable precision therapies targeting neuroimmune circuits, thereby overcoming the limitations of hemodynamic-focused care. This mechanistic framework shifts the therapeutic paradigm from symptomatic relief to targeted modulation of pathogenic pathways, with implications for millions of patients with cardiomyopathy and broader inflammatory cardiovascular disorders.

Immuno doi: 10.3390/immuno5040044

Authors: Natalia P. Maltseva Ksenja A. Riabova Yury V. Zhernov

Inducible forms of chronic urticaria are characterized by an early age of onset and a long duration of disease. In addition, cold and cholinergic urticaria have a risk of developing systemic, sometimes life-threatening, reactions. Determining the pathogenetic mechanisms and laboratory and clinical predictors of their development is an open question in the understanding of these diseases. This literature review demonstrates the current known facts that allow the identification of patients with cold and cholinergic urticaria in high-risk groups of anaphylaxis development and, therefore, the possibility to prevent emergency situations and to manage them in time. For cold and cholinergic urticaria, observations of Kounis syndrome–acute coronary syndrome (myocardial infarction or unstable angina) have been described. A series of trials, including the large international multicenter COLD-CE study of anaphylaxis in cold urticaria, have identified early age of urticaria onset, severe clinical symptoms, shortening of the critical temperature threshold, comorbid bronchial asthma, concomitant angioedema, and pruritus of the earlobes as warning signs. No such large-scale studies have been conducted for cholinergic urticaria. Among the few high-risk factors for systemic reactions in cholinergic urticaria described in the literature is the occurrence of angioedema. Thus, it is possible to identify some patients in the high-risk group already at the stage of initial anamnesis collection, and additional data can be collected during the examination. Laboratory biomarkers, clinical predictors, understanding the mechanisms of anaphylaxis by physical triggers or their consequences, and optimal options for pathogenetic therapy are still unresolved issues that require further research. The aim of this review is to provide a content analysis of current knowledge about chronic inducible urticarias in order to increase clinicians’ awareness and, consequently, reduce the risk of urgent conditions associated with them.

Immuno doi: 10.3390/immuno5030043

Authors: Igor D. Zlotnikov Natalia I. Kolganova Shamil A. Gitinov Dmitry Y. Ovsyannikov Elena V. Kudryashova

Addressing the critical challenge in the differential diagnosis of severe inflammatory lung diseases, we propose a novel methodology for the analysis of macrophage surface receptors, CD68 and CD206, using specific non-antibody ligands. We developed a non-antibody alternative for the fluorometric detection of CD68+ cells, focusing on macrophages as key functional markers in inflammatory processes. Our marker based on dioleylphosphatidylserine (DOPS), a specific ligand to CD68, was incorporated into a liposomal delivery system. The specificity of this DOPS-based ligand can be precisely modulated by the liposome’s composition and the polyvalent presentation of the ligand. We synthesized a series of fluorescently-labeled DOPS-based ligands and developed a liposome-based sandwich fluorometric assay. This assay enables the isolation and quantification of CD68 receptor presence from bronchoalveolar lavage fluid (BALF). The results confirmed the specific binding of DOPS/lecithin liposomes to CD68+ cells compared to control lecithin systems. Furthermore, the incorporation of PEGylated ‘stealth’ liposomes significantly enhanced binding specificity and facilitated the generation of distinct binding profiles, which proved valuable in differentiating various inflammatory conditions. This approach yielded unique binding profiles of PS-based ligands to CD68+ cells, which varied significantly among a broad range of respiratory conditions, including primary ciliary dyskinesia, bronchial asthma, bronchitis, bacterial infection, pneumonia, and bronchiectasis. Confocal Laser Scanning Microscopy demonstrated selective binding and intracellular localization of the DOPS-based marker within CD68+ macrophages from BALF samples of patients with bronchitis or asthma. The binding parameters of this multivalent composite ligand with the CD68 receptor are comparable to those of antibodies. The inherent binding specificity of phosphatidylserine may offer a sufficient and viable alternative to conventional antibodies. Our results demonstrate the remarkable potential of this novel DOPS-based assay as a complementary tool for the developing non-antibody-based systems for the differential diagnosis of the respiratory diseases, warranting further investigation in larger clinical studies.

Immuno doi: 10.3390/immuno5030042

Authors: Samudra Lansakara Janis Weis Chathura Siriwardhana Yongsoo Kim

Rheumatoid arthritis synovial fibroblasts (RASFs) play a pivotal role in joint destruction in RA. Myostatin (MSTN), a myokine, is highly expressed in the RA synovium; however, its role in the function of RASFs is unclear. We hypothesized that MSTN amplifies inflammatory cytokines/chemokines, promotes RASF invasion, and facilitates CD4+ Th cell transmigration. Immortalized MH7A cells (RASFs) and healthy synovial fibroblasts (HSFs) were treated with MSTN (0, 10, 20 ng/mL) for 0, 24, and 48 h. Cytokines (IL-8, IL-17, TNF-α, IL-6, IL-23, IFN-γ, IFN-β) and chemokines (CCL2, CCL20, CXCL13, CXCL1) were quantified by ELISA, RT-qPCR, and Western blotting. To evaluate MSTN regulation, cells were treated with pro-inflammatory mediators (TNF-α, IL-17, IFN-γ, IFN-β, CCL2, CXCL1). MSTN’s effects on Thy-1(CD90)+ RASF/HSF proliferation, RASF invasion, and CD4+ T-cell transmigration were assessed. Compared with HSFs, RASFs exhibited greater proliferative activity. MSTN significantly upregulated cytokines/chemokines, with CXCL1 showing the strongest induction in RASFs. IFN-γ and IL-17 robustly increased MSTN expression, indicating a feed-forward loop. MSTN did not alter Thy-1(CD90)+ fibroblast proliferation but significantly enhanced RASF invasion and CD4+ T-cell transmigration. Neutralizing CXCL1 or IL-17 reduced transmigration, with stronger inhibition via CXCL1. These findings offer new insights into the role of MSTN in RA pathogenesis and highlight its potential as a therapeutic target.

Immuno doi: 10.3390/immuno5030041

Authors: Ryuichi Ohta Taichi Fujimori Chiaki Sano Kunihiro Ichinose

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by immune-mediated β-cell destruction, where interleukin-6 (IL-6) signaling plays a complex and context-dependent role. Tocilizumab, an IL-6 receptor (IL-6R) inhibitor, is effective in several autoimmune conditions, but its influence on the onset and progression of T1DM remains uncertain. This scoping review aimed to map current clinical, genetic, and mechanistic evidence linking IL-6/IL-6R signaling to T1DM risk and to identify key research gaps. Following PRISMA-ScR guidelines, PubMed, Embase, and Web of Science were searched for studies from 2005 to 2025 reporting associations between tocilizumab or IL-6R modulation and T1DM onset. Six studies were included: one case report describing T1DM onset during tocilizumab therapy in a genetically predisposed patient, one randomized controlled trial showing no significant β-cell preservation with tocilizumab, three Mendelian randomization analyses with conflicting findings on IL-6R signaling, and one mechanistic study showing enhanced IL-6 responsiveness in early-stage T1DM. Collectively, evidence remains fragmented and inconclusive, highlighting research gaps in the differential roles of IL-6 classic versus trans-signaling and the impact of genetic predisposition. Future prospective studies should clarify whether selective IL-6 trans-signaling blockade may offer safer, targeted strategies for modulating autoimmune β-cell destruction.

Immuno doi: 10.3390/immuno5030040

Authors: Nunzia Porro Elena Spínola-Lasso Fabio Marra Alessandra Gentilini

Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive and heterogeneous malignancy characterized by marked resistance to standard chemotherapy and poor prognosis. While the advent of immunotherapy has revolutionized the management of several solid tumors, including melanoma, breast cancer, and non-small cell lung cancer, its efficacy in iCCA remains limited. Recent clinical trials have demonstrated the efficacy of durvalumab in combination with chemotherapy for iCCA, leading to its approval as a first-line treatment. However, overall response rates remain low, largely due to its immunosuppressive tumor immune microenvironment (TIME). The immune-cold nature of iCCA is typified by a dominant presence of immunosuppressive cell populations, including M2-polarized tumor-associated macrophages, myeloid-derived suppressor cells, and T regulatory cells. In addition, traditional biomarkers such as PD-L1 expression, tumor mutational burden, and microsatellite instability have shown limited predictive value in iCCA, highlighting the need for novel biomarkers and immunotherapeutic strategies. Emerging approaches aimed at reprogramming the TIME, including combination therapies targeting suppressive cells, stromal remodeling, and novel immune effectors like CAR-T and cancer vaccines, hold significant promise for enhancing therapeutic efficacy. This review summarizes the distinct features of iCCA TIME, key mechanisms of immune evasion, current challenges, and future directions to overcome immune resistance, with the aim of developing personalized immunotherapies to improve patient outcomes.

Immuno doi: 10.3390/immuno5030039

Authors: Chy’as Diuranil Astrid Permataputri Purwo Sri Rejeki Raden Argarini Shariff Halim Sheeny Priska Purnomo Dian Aristia Rachmayanti

Background/Objectives: Obesity induces chronic low-grade inflammation marked by elevated pro-inflammatory cytokines, such as interferon-gamma (IFN-γ), and reduced anti-inflammatory cytokines like interleukin-10 (IL-10), contributing to immune dysregulation. Intermittent fasting (IF) may restore immune balance through metabolic and circadian mechanisms. This study compared the effects of time-restricted eating (TRE) and alternate-day modified fasting (ADMF) on IFN-γ and IL-10 levels in young women with obesity. Methods: A 20-day quasi-experimental study with a pretest–posttest control group design included 23 non-diabetic women with obesity (aged 18–25 years; BMI ≥ 25 kg/m2 according to the Asia-Pacific classification), randomized into control (n = 8), TRE 18:6 (n = 8), and ADMF (n = 7) groups. IFN-γ and IL-10 serum levels were measured pre- and post-intervention using ELISA kits. Results: TRE significantly reduced IFN-γ levels (p = 0.025), while no significant change was observed in the ADMF or control groups. No significant changes were found in IL-10 levels. Conclusions: TRE effectively reduced pro-inflammatory IFN-γ levels without significantly altering anti-inflammatory IL-10 levels, suggesting an anti-inflammatory effect primarily mediated through suppression of IFN-γ rather than IL-10 upregulation. The absence of significant IL-10 changes may reflect complex immunoregulatory dynamics in obesity. ADMF showed no significant immunomodulatory impact. These findings support TRE as a promising non-pharmacologic strategy to attenuate inflammation and improve immune balance in young women with obesity.

Immuno doi: 10.3390/immuno5030038

Authors: Mohamed A. Eltokhy Bhaumik Patel Marina Curcic Faizah Alabi Shadan Modaresahmadi Omar Eltoukhy Esraa G. Abdelmageed Sahar Radwan

Viral infection is a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (Allo-HSCT), largely due to its impact on and interaction with immune reconstitution. Both innate and adaptive immunity are essential for effective viral control, yet their recovery post-transplant is often delayed or functionally impaired. Emerging evidence suggests genetic variation, particularly polymorphisms in the IL28B gene (encoding IFN-λ3), as a critical factor influencing the quality and timing of immune responses during the early post-transplant period. This review explores the role of IL28B polymorphisms in shaping antiviral immunity, in general, as well as after Allo-HSCT. IL28B variants have been implicated in modulating interferon-stimulated gene (ISG) expression, natural killer (NK) cell activity, and type I/III interferon signaling, all central components of innate immune defense against viral infections. Furthermore, IL28B polymorphisms, particularly rs12979860, have been shown in both general populations and limited HSCT cohorts to alter T cell response and interferon production, affecting reactivation and clearance of multiple viruses such as cytomegalovirus (CMV), hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein–Barr virus (EBV), COVID-19, and BK polyomavirus (BKPyV) as well as Graft vs. Host disease, thereby affecting adaptive immune reconstitution and long-term viral control. Understanding how IL28B genotype alters immune dynamics in transplant recipients could enhance risk stratification for CMV and other diseases and inform personalized prophylactic or therapeutic strategies. Therefore, this review highlights IL28B as a promising biomarker and potential immunoregulatory target in the management of viral infection post-Allo-HSCT.

Immuno doi: 10.3390/immuno5030037

Authors: Yvonne C. F. Pang Wei Jen Ma Susan C. Menzies Laura M. Sly

Crohn’s disease is a chronic, idiopathic inflammatory bowel disease characterized by patchy, transmural inflammation that is influenced by genetic, environmental, and microbial factors. The NOD2 pathway mediates NFκB activation and pro-inflammatory cytokine production. In the SHIP–/– murine model of Crohn’s disease-like ileitis, macrophage-derived IL-1β production drives intestinal inflammation. SHIP reduces NOD2 signaling by preventing downstream interaction between RIPK2 and XIAP, leading us to hypothesize that blocking RIPK2 in SHIP–/– mice would ameliorate intestinal inflammation. We examined the effects of RIPK2 inhibition on pro-inflammatory cytokine production in SHIP+/+ and SHIP–/– macrophages and in mice, using the RIPK2 inhibitor, GSK2983559. We found that GSK2983559 blocked RIPK2 activation in SHIP+/+ and SHIP–/– bone marrow-derived macrophages (BMDMs), and reduced Il1b transcription and IL-1β production in (MDP+LPS)-stimulated SHIP–/– BMDMs. Despite the reduction of IL-1β production in BMDMs, in vivo treatment with GSK2983559 worsened intestinal inflammation and increased IL-1β concentrations in the ileal tissues of SHIP–/– mice. GSK2983559 only modestly reduced IL-1β in (MDP+LPS)-stimulated SHIP–/– peritoneal macrophages, and did not suppress pro-inflammatory cytokine production in response to TLR ligands in peritoneal macrophages from either SHIP+/+ or SHIP–/– mice. Taken together, our data suggest that although RIPK2 inhibition can block IL-1β production by (MDP+LPS)-stimulated macrophages in vitro, it is not an effective anti-inflammatory strategy in vivo, highlighting the limitations of targeting RIPK2 to treat intestinal inflammation in the context of SHIP deficiency.

Immuno doi: 10.3390/immuno5030036

Authors: Bashar Saad Abdalsalam Kmail

Olive oil, a cornerstone of the Mediterranean diet, is increasingly recognized not only for its cardiovascular benefits but also for its potential role in cancer prevention and therapy. Among its bioactive constituents, several phenolic compounds—tyrosol, hydroxytyrosol, oleuropein, oleacein, and oleocanthal—have demonstrated promising anticancer activities in various experimental models. These compounds act synergistically through diverse mechanisms, including antioxidant, anti-inflammatory, and immunomodulatory effects, as well as modulation of cell proliferation, apoptosis, angiogenesis, and metastasis. Notably, oleocanthal selectively induces cancer cell death via lysosomal membrane permeabilization, while hydroxytyrosol and oleuropein exhibit potent radical-scavenging and anti-proliferative properties. This review synthesizes findings from in vitro, in vivo, and clinical studies on the anticancer potential of these polyphenols, with emphasis on their mechanisms of action and possible applications in cancer prevention and adjunctive therapy. Given the established link between obesity and cancer development, clinical studies examining the metabolic, anti-inflammatory, and immunomodulatory effects of olive polyphenols in populations with obesity or prediabetes provide valuable insights into their potential to influence cancer-related pathways indirectly. However, direct clinical evidence in cancer patients remains limited and preliminary, underscoring the need for focused, well-controlled trials with cancer-specific endpoints. Furthermore, it critically evaluates the translational relevance of these findings, highlighting gaps in clinical research and future directions. Literature was retrieved from Google Scholar, PubMed, and ScienceDirect using keywords such as cancer, immunomodulatory, anti-inflammatory, olive, tyrosol, hydroxytyrosol, oleuropein, oleacein, and oleocanthal. Given the rising global cancer burden and the favorable safety profiles of these natural molecules, elucidating their molecular actions may support the development of novel integrative therapeutic strategies.

Immuno doi: 10.3390/immuno5030035

Authors: Steliyan Petrov Martina Bozhkova Mariya Ivanovska Teodora Kalfova Alexandra Baldzhieva Angel Todev Dilyana Kirova Yoana Kicheva Stoyno Stoynov Marianna Murdjeva Hristo Taskov

The immune response to SARS-CoV-2 infection involves significant alterations in the phenotype and function of natural killer (NK) cells. This study aimed to investigate the dynamic changes in NK cell subsets during COVID-19 by analyzing their activation and inhibitory markers [CD3, CD14, CD16, CD19, CD25, CD45, CD56, CD57, CD69, CD159a (NKG2A), CD159c (NKG2C), CD314 (NKG2D), CD335 (NKp46)], cytotoxic potential (perforin, interferon-gamma, granzyme B), and direct cytotoxicity against a newly genetically modified K562 cell line. Peripheral blood samples were collected from COVID-19 patients on days 3–5 and day 30 post-symptom onset and were compared to healthy controls. 16-color flow cytometry analysis revealed distinct shifts in NK cell subpopulations, characterized by increased expression of the inhibitory receptor NKG2A and the activating receptors NKG2D and NKG2C, particularly in the CD56+CD16− subset. Elevated IFN-γ production on day 30 suggested a recovery-phase immune response, while the persistent upregulation of NKG2A indicated an ongoing regulatory mechanism. The CD16+CD56− subpopulation exhibited increased expression of the markers CD69 and CD25 over time; however, its cytotoxic potential, assessed through granzyme B levels and direct cytotoxicity assays, remained lower than that of healthy controls. Significant correlations were observed between CD57 and CD69 expression, as well as NKp46 and IFN-γ production, highlighting a coordinated balance between activation and regulatory mechanisms. These findings suggest that NK cells undergo functional adaptation during COVID-19, displaying signs of partial exhaustion while retaining antiviral potential. Understanding the interplay between NK cell activation and suppression may provide valuable insights into immune dysregulation in COVID-19 and inform potential therapeutic interventions.

Immuno doi: 10.3390/immuno5030034

Authors: Joel Henrique Ellwanger Jacqueline María Valverde-Villegas Marina Ziliotto José Artur Bogo Chies

The human C-C chemokine receptor type 5 (CCR5) is a molecule primarily expressed on the surface of inflammatory cells, acting as the main HIV co-receptor. In order to penetrate host cells, HIV interacts with both CCR5 and the CD4 molecule during the infectious process. Emerging evidence suggests that pollution by metals, such as aluminum, lead, and manganese, triggers CCR5-mediated inflammation, which may have important implications for the risk of HIV infection. Specifically, we hypothesize that exposure to pollution by metals causes inflammation and elevated CCR5 expression on the surface of CD4+ cells, resulting in an increased risk of HIV infection. Our hypothesis is supported by toxicogenomic data, which shows that both air pollutants and some metals (e.g., arsenic, cadmium, nickel) induce CCR5 expression. Finally, approaches to evaluate the hypothesis are suggested. If confirmed, our hypothesis introduces environmental pollution to the set of biological factors influencing the risk of HIV infection.

Immuno doi: 10.3390/immuno5030033

Authors: Pabeli Saraí Becerra-Romero Cynthia Fernández-Pomares Juan Carlos Rodríguez-Alba Jorge Manzo Gonzalo E. Aranda-Abreu Fausto Rojas-Durán Deissy Herrera-Covarrubias María Rebeca Toledo-Cárdenas Genaro Alfonso Coria-Ávila Maria Elena Hernández-Aguilar

The prostate gland, a male accessory reproductive organ, is regulated by hormonal inputs and autonomic innervation from the major pelvic ganglion. This study examined the effects of major pelvic ganglion denervation on prostate histology, immune cell infiltration, and systemic levels of prolactin, testosterone, and cytokines in rats. Male Wistar rats (300–350 g) were divided into groups receiving bilateral axotomy of the hypogastric nerve, the pelvic nerve, or both, alongside with a sham-operated control. After 15 days, the animals were killed, and prostate tissue was dissociated in DMEM medium containing DNase I and collagenase. The dissociated cells were stained with fluorochrome-conjugated antibodies, and cell characterization was performed using a flow cytometer. Hematoxylin and eosin (H&E) staining was used to analyze histological characteristics, while testosterone, prolactin, and interleukin levels were measured via ELISA. Histological analysis revealed inflammatory atypical hypertrophy e hiperplasia. Immunological assessments demonstrated increased leukocytes, T lymphocytes (CD4+ and CD8+), B lymphocytes, and macrophages following double nerve axotomy. Serum analyses showed elevated pro-inflammatory cytokines IL-1β, IL-6, and IFN-γ, as well as anti-inflammatory IL-10, in denervated animals. Hormonal assessments revealed significant increases in serum prolactin and testosterone levels after double axotomy. Loss of neural control may promote pathological prostate changes via inflammation and hormonal dysregulation, offering insights into neuroimmune and neuroendocrine mechanisms underlying prostate pathologies.

Immuno doi: 10.3390/immuno5030032

Authors: Rita Khoury Annoir Shayya Cendrella Bou Orm Osama Zein Deen Hady Ghanem

Immunotherapy has revolutionized cancer treatment. Despite its success across various malignancies, a significant proportion of patients either fail to respond (primary resistance) or relapse after an initial response (acquired resistance). This review explores the different mechanisms underlying resistance to immunotherapy, including tumor-intrinsic factors such as loss of antigen presentation, genetic, and epigenetic mutations. It also examines tumor-extrinsic contributors, such as immunosuppressive cells in the tumor microenvironment, checkpoint molecule upregulation, and microbiome influences. A comprehensive understanding of resistance mechanisms is essential for improving patient selection, developing combination therapies, and ultimately enhancing the efficacy and durability of immunotherapeutic interventions.

Immuno doi: 10.3390/immuno5030031

Authors: Mayara Bocchi Eduardo Vignoto Fernandes Nathália de Sousa Pereira Marla Karine Amarante

Human colorectal cancer (CRC) encompasses tumors affecting a segment of the large intestine (colon) and rectum. It is the third most commonly diagnosed malignancy and the second leading cause of cancer deaths worldwide. It is a multifactorial disease, whose carcinogenesis process involves genetic and epigenetic alterations in oncogenes and tumor suppressor genes, including genes related to DNA repair. The pathogenic mechanisms are described based on the pathways of chromosomal instability, microsatellite instability, and CpG island methylator phenotype. When detected early, CRC is potentially curable, and its treatment is based on the pathological characteristics of the tumor and factors related to the patient, as well as on drug efficacy and toxicity studies. Therefore, the aim of this study was to review the pathogenesis and molecular subtypes of CRC and to describe the main targets of disease-directed therapy used in patients refractory to current treatments.

Immuno doi: 10.3390/immuno5030030

Authors: Nina Quirk Rohan Ahuja Nirav Thosani

Despite advances in surgery, chemotherapy, and radiation treatments for pancreatic ductal adenocarcinoma (PDAC), 5-year survival rates remain at nearly 11%. Cholangiocarcinoma, while not as severe, also possesses similar survival rates. Fewer than 20% of patients are surgical candidates at time of diagnosis; therefore, it is imperative that alternative therapies are effective for non-surgical patients. There are several thermal ablative techniques, including radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), microwave ablation (MWA), alcohol ablation, stereotactic body radiotherapy (SBRT), cryoablation, irreversible electroporation (IRE), biliary intraluminal brachytherapy, and biliary photodynamic therapy (PDT). Emerging literature in animal models and human patients has demonstrated that endoscopic ultrasound (EUS)-guided RFA (EUS-RFA) prevents tumor progression through coagulative necrosis, protein denaturation, and activation of anticancer immunity in local and distant tumor tissue (abscopal effect). RFA treatment has been shown to not only reduce tumor-associated immunosuppressive cells but also increase functional T cells in distant tumor cells not treated with RFA. The remarkable ability to reduce tumor progression and promote tumor microenvironment (TME) remodeling makes RFA a very promising non-surgical therapy technique that has the potential to reduce mortality in this patient population. EUS-RFA offers superior precision and safety compared to other ablation techniques for pancreatic and biliary cancers, due to real-time imaging capabilities and minimally invasive nature. Future research should focus on optimizing RFA protocols, exploring combination therapies with chemotherapy or immunotherapy, and expanding its use in patients with metastatic disease. This review article will explore the current data and underlying pathophysiology of EUS-RFA while also highlighting the role of ablative therapies as a whole in immune activation response.

Immuno doi: 10.3390/immuno5030029

Authors: Alina Miruna Grecea-Balaj Olga Soritau Ioana Brie Maria Perde-Schrepler Piroska Virág Nicolae Todor Tudor Eliade Ciuleanu Cosmin Andrei Cismaru

The tumor microenvironment (TME) in advanced solid tumors is determined by immune checkpoints (PD-1, CTLA-4, and CD95) and cytokine networks (IL-2, IL-10, and TNF-α) that drive CD8+ T cell exhaustion, metabolic reprogramming, and apoptosis resistance, enabling immune evasion. Some studies revealed PD-1/CD95 co-expression is a marker of T cell dysfunction, while CTLA-4 upregulation correlates with suppressed early T cell activation. IL-10 has emerged as a potential biomarker for chemoresistance and tumor aggressivity, consistent with its role in promoting anti-apoptotic signaling in cancer stem cells (CSCs). Engineered IL-2 variants and TNF-α modulation are highlighted as promising strategies to revitalize exhausted CD8+ T cells and disrupt CSC niches. This prospective single-center study investigated the dynamic TME alterations in 16 patients with immunotherapy-naïve stage IV non-small-cell lung cancer (NSCLC) and metastatic melanoma treated with anti-PD-1 nivolumab. The longitudinal immunophenotyping of peripheral blood lymphocytes (via flow cytometry) and serum cytokine analysis (via ELISA) were performed at the baseline, >3, and >6 months post-treatment to evaluate immune checkpoint co-expression (PD-1/CD95 and CTLA-4/CD8+) and the cytokine profiles (IL-2, IL-10, and TNF-α).

Immuno doi: 10.3390/immuno5030028

Authors: Gustavo Alberto Obando-Pereda Luis Alberto Ponce-Soto

Guillain-Barre syndrome is an autoimmune disease that provokes neural illness causing acute paralysis neuropathy. This syndrome appears after some bacterial infections produced by Campylobacter jejuni, Streptococcus pyogenes, S. pneumoniae, Haemophilus influenciae, E. coli and current studies showed the appears of this syndrome after SARS-CoV-2 infection. In this study, a in silico analysis was carry out in which to determinate bacterial epitopes than produce the molecule mimicry phenomena and that can produce the immune system activation against this epitope. A conserved amino acid sequence has been encountered with the highest probability to activate the immune system against this bacterial epitope, human gliomedin and ryanodine 3 type receptor. More studies needed to demonstrate in vivo the molecular mimicry in Guillain-Barre syndrome patients.

Immuno doi: 10.3390/immuno5030027

Authors: Achilleas P. Galanopoulos Sofia Raftopoulou Styliani Sarrou Alexia Matziri Stamatia Papoutsopoulou Grigorios Stratakos Varvara A. Mouchtouri Martin Hölzer Christos Hadjichristodoulou Fani Kalala Matthaios Speletas

Predominantly antibody deficiencies (PADs) are the most prevalent types of inherited errors of immunity (IEI) and are characterized by a broad range of clinical manifestations, such as recurrent infections, autoimmunity, lymphoproliferation, atopy and malignancy. The aim of this study was to identify genetic defects associated with PADs in order to improve diagnosis and personalized care. Twenty patients (male/female: 12/8, median age of disease onset: 16.5 years, range: 1–50) were analyzed by next-generation sequencing (NGS) using a custom panel of 30 genes associated with PADs and their possible disease phenotype. The detected variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and inheritance, and the penetrance patterns were evaluated by PCR–Sanger sequencing. Novel and rare mutations associated with the phenotype of common variable immunodeficiency (CVID) in genes encoding the transcription factors NFKB1, NFKB2 and IKZF1/IKAROS were identified. Alphafold3 protein structure prediction was utilized to perform a comprehensive visualization strategy and further delineate the mutation-bearing domains and elucidate their potential impact on protein function. This study highlights the value of genetic testing in PADs and will guide further research and improvement in diagnosis and treatment.

Immuno doi: 10.3390/immuno5030026

Authors: Simin Farokhi Seyed Mehdi Tabaie Arshia Fakouri Shirin Manshouri Nikoo Emtiazi Ayda Sanaei Mohammad Mahjoor Amir Mohammad Akbari Ali Daneshvar Farhad Seif

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a multifaceted inflammatory disorder characterized by distinct immunopathogenic entities, including type 2 inflammation mediated by cytokines such as interleukin-4 (IL-4), IL-5, and IL-13. These cytokines contribute to eosinophilic inflammation, epithelial barrier dysfunction, and mucus overproduction, resulting in polyp formation. Advances in molecular understanding have resulted in the identification of CRSwNP endotypes, suggesting personalized treatment approaches. Conventional therapies, such as intranasal and systemic corticosteroids, provide symptom relief but are restricted by side effects and polyp recurrence, necessitating the development of novel targeted approaches. Biologic therapies represent a breakthrough in CRSwNP management. Monoclonal antibodies such as dupilumab, omalizumab, mepolizumab, and Benralizumab (IL-5 receptor alpha) target key mediators of type 2 inflammation, leading to substantial improvements in polyp size, symptom control, and quality of life. Additionally, emerging therapies like tezepelumab and brodalumab aim to address broader immune mechanisms, including type 1 and type 3 inflammation. These advancements enable tailored treatment approaches that optimize outcomes and reduce reliance on surgical interventions. Biomarker-driven research continues to refine CRSwNP classification and treatment efficacy, emphasizing precision medicine. Future efforts should focus on expanding the therapeutic landscape, investigating long-term impacts of biologics, and exploring their combinatory potential to improve disease control. This review discusses the role of innate and adaptive immunity in the pathogenesis of CRSwNP and suggests novel cytokine-targeted strategies for further considering personalized medicine in future therapeutic plans.

Immuno doi: 10.3390/immuno5030025

Authors: Jenny Valentina Garmendia Juan Bautista De Sanctis Alexis Hipólito García

IgG antibodies, particularly those of the IgG4 subclass, have generated significant debate regarding their role in immune tolerance versus food intolerance. This article comprehensively reviews the literature on the subject, exploring evidence from healthy individuals and patient populations with varied clinical conditions. On one hand, IgG—especially IgG4—is frequently detected in individuals without adverse food reactions and may represent a normal adaptive immune response to constant dietary antigen exposure, contributing to the development of regulatory T-cell–mediated tolerance. On the other hand, several studies have linked elevated food-specific IgG levels with conditions characterized by increased intestinal permeability and inflammation, including eosinophilic esophagitis, irritable bowel syndrome, inflammatory bowel disease, and autoimmune disorders. The review discusses multiple investigations where IgG-guided elimination diets have yielded symptomatic improvements, suggesting a potential benefit for targeted dietary interventions. However, these findings are tempered by the observation that IgG antibodies are commonly present in asymptomatic individuals, thereby questioning their specificity as markers of adverse food reactions. Current diagnostic guidelines from leading allergy and immunology organizations discourage routine IgG testing for food allergies and intolerances, highlighting that these antibodies might instead indicate exposure or underlying inflammation rather than an actual pathogenic mechanism. There is a need for well-controlled, large-scale studies to clearly define the clinical relevance of food-specific IgG responses. Until more substantial evidence is provided, clinicians are advised to interpret the IgG results cautiously and to consider them within the broader context of each patient’s clinical presentation before recommending restrictive dietary changes.

Immuno doi: 10.3390/immuno5030024

Authors: Konstantinos Pavlidis Theodora Adamantidi Chatzikamari Maria Karamanis Georgios Vasiliki Dania Xenophon Krokidis Alexandros Tsoupras

Sjögren’s syndrome (SS) is a chronic autoimmune disease primarily affecting the lacrimal and salivary glands, characterized by ocular and oral dryness. Beyond exocrine dysfunction, SS may also involve multiple organs and systems, contributing to systemic complications that impair a patient’s quality of life. Among these, ocular inflammation represents a significant clinical challenge, manifesting as dry eye disease and other vision-affecting complexities. Despite advances in SS understanding, the inflammatory mechanisms driving ocular manifestations remain incompletely elucidated. This review aims to clarify the key inflammatory pathways underlying ocular complications in SS and the clinical implications. Additionally, it discusses both conventional and novel therapeutic strategies focusing on mitigating SS-associated ocular inflammation, including targeted immunomodulatory agents, regenerative medicine, and innovative drug delivery systems. By integrating current knowledge from recent studies, this review attempts to provide researchers and clinicians with a comprehensive resource for optimizing SS treatment approaches. The advancement of targeted therapies and emerging mitigation strategies holds promise for improving patient outcomes and enhancing SS management.

Immuno doi: 10.3390/immuno5030023

Authors: Paula D. Morales-Suárez Yina T. Zambrano-O Alejandro Mejía-Garcia Hsuan Megan Tsao Liliana Lopez-Kleine Diego A. Bonilla Alba L. Combita Rafel Parra-Medina Patricia Lopez-Correa Silvia J. Serrano-G Juliana L. Rodriguez Carlos A. Orozco

Background: High-grade serous ovarian cancer (HGSOC) is a highly aggressive malignancy with poor prognosis due to late-stage diagnosis and limited treatments. Identifying differentially expressed genes (DEGs), and immune cell infiltration patterns may improve prognostic assessment and therapeutic strategies. Methods: We conducted a meta-analysis of gene expression data from the GEO (Gene Expression Omnibus, NCBI). DEGs were identified, functionally enriched, and analyzed for protein-protein interactions. Overlaps with oncogenes and tumor suppressor genes were examined. Cox survival analysis and a gene expression-based risk stratification model were developed. Immune infiltration differences were assessed using deconvolution methods. Results: A total of 11 studies (291 HGSOC, 96 controls) identified 892 DEGs, mainly involved in mitochondrial function, vesicle trafficking, and immune regulation. Key oncogenes (EZH2, PDK1, ERBB2) and tumor suppressor genes (BRCA1, DUSP22) were identified. Survival analysis associated the expression of SEC24B, TGOLN2, TRAK1, and CAST with poor prognosis. Low-risk patients had higher activated dendritic cells and CD4+ memory T cells while high-risk patients were enriched in common lymphoid progenitors and megakaryocyte-erythroid progenitors. Conclusions: This study identifies key DEGs in HGSOC progression and presents a risk stratification model predicting patient outcomes.

Immuno doi: 10.3390/immuno5020022

Authors: Dimitar Dimitrov Antoaneta Mlachkova Marina Miteva Dimitar Parvanov Velitchka Dosseva-Panova

The sympathetic nervous system (SNS) is crucial for stress response regulation and immune modulation. Prolonged SNS activation, often induced by stress exposure, disrupts immune homeostasis and intensifies inflammatory processes, contributing to periodontal disease progression. This study investigates the relationship between SNS activity and periodontitis severity, utilizing salivary biomarkers chromogranin A (CgA) and alpha-amylase (sAA) alongside pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-6 (IL-6). Saliva samples from 67 patients, categorized by periodontitis severity (Stages I/II and III/IV), were analyzed using enzyme-linked immunosorbent assay (ELISA). The results revealed significantly higher median levels of CgA (9.45 vs. 3.93 pmol/mL) and IL-1β (257.81 vs. 220.11 pg/mL) in patients with Stage III/IV periodontitis compared with those with Stage I/II, indicating heightened SNS activity and inflammatory response. Correlations between these biomarkers and clinical periodontal parameters, such as probing depth and clinical attachment loss, further support these findings. Despite elevated sAA levels in severe cases, statistical significance was not achieved. IL-6 levels also showed no significant variation across disease stages, although trends aligned with increased severity. This study highlights the interplay between SNA activation and periodontal inflammation, as evidenced by elevated salivary levels of CgA and IL-1β in patients with advanced periodontitis. By integrating neuroendocrine and inflammatory biomarkers into the diagnostic process, clinicians may be able to better identify patients at increased risk for periodontal breakdown and to consider adjunctive interventions such as stress management, thereby supporting more personalized approaches to periodontitis treatment.

Immuno doi: 10.3390/immuno5020021

Authors: Ketevan Lomidze Nino Kikodze Marine Gordeladze Nino Charkviani Tinatin Chikovani

Background: A novel and highly effective strategy for tumor immunotherapy involves enhancing host immune responses against tumors through the blockade of checkpoint molecules. The most common toxicities associated with checkpoint blockade therapies include autoimmune damage to various organs. Purpose: This study aims to investigate hematological markers derived from complete blood counts (CBCs)—including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), derived neutrophil-to-lymphocyte ratio (dNLR), white blood cell-to-hemoglobin ratio (WHR), neutrophils, lymphocytes, platelets, hemoglobin, red blood cell (RBC) count, neutrophil-to-RBC ratio (NRR), and neutrophil-to-hemoglobin ratio (NHR)—as potential prognostic biomarkers for the early identification of hypothyroidism in patients receiving PD-1 or PD-1/CTLA-4 immune checkpoint inhibitors. Materials and Methods: A prospective observational study was conducted on 44 patients with stage III-IV solid tumors treated with immune checkpoint (PD-1 or PD-1/CTLA-4) inhibitors. Thyroid function tests and CBC-derived biomarkers were collected at baseline, before immunotherapy. In the immunotherapy cohort, 15 of the 44 patients developed immune-related hypothyroidism, defined as overt autoimmune thyroiditis (TSH > 4.0, FT4 < 12, and anti-TPO antibodies > 30 IU/mL and/or anti-TG antibodies > 95 IU/mL) (Group 1). In comparison, 29 patients maintained normal thyroid function (Group 2). The control group comprised 14 age- and sex-matched healthy volunteers (Group 3). Statistical analyses were performed using analysis of variance (ANOVA) to compare blood parameters among the three groups (Group 1, Group 2, and Group 3) before treatment, with statistical significance set at a p-value < 0.05. Receiver operating characteristic (ROC) curve analysis was conducted to evaluate the diagnostic power of the potential prognostic biomarkers areas. The area under the curve (AUC), sensitivity, and specificity were calculated for the 44 immunotherapy patients. Results: The PLR was significantly higher (262.25 ± 162.95), while WBCs-neutrophils, the WHR, the NRR, the NHR, WBCs, neutrophils, and lymphocytes were lower (2.07 ± 0.66, 0.54 ± 0.19, 0.96 ± 0.28, 0.36 ± 0.14, 6.36 ± 2.07, 4.29 ± 1.55, and 1.23 ± 0.41, respectively) at baseline in Group 1 in comparison to Group 2. ROC curve analysis revealed that the areas under the curve (AUC) for WBCs, neutrophils, lymphocytes, WBCs-neutrophils, the PLR, the WHR, the NRR, and the NHR were 0.9, 0.87, 0.83, 0.85, 0.84, 0.92, 0.89, and 0.87, respectively. These values exceeded the threshold, indicating the high prognostic potential of each marker. Conclusions: Lower baseline levels of WBCs-neutrophils, the WHR, the NRR, the NHR, WBCs, neutrophils, and lymphocytes, along with a higher PLR, were associated with an increased risk of hypothyroidism in patients receiving PD-1 or PD-1/CTLA-4 inhibitors. These CBC-derived biomarkers represent simple, accessible, and potentially useful tools for predicting hypothyroidism in cancer patients undergoing immunotherapy. Further studies in bigger cohorts are needed to validate our findings.

Immuno doi: 10.3390/immuno5020020

Authors: Daniel Rodriguez-Pinto María Sol Mendoza-Ruiz

Antibody-dependent enhancement (ADE) is a well-established mechanism of pathology in several viral diseases, but its relevance in COVID-19 is not yet recognized. Although several studies in humans have shown an association between antibody responses and disease severity, long term studies addressing the presence of antibodies before infection and their neutralization capacity are needed to establish ADE. Mechanistic studies have determined that the entry of SARS-CoV-2 into host cells can be mediated by immune complexes through Fcγ receptors or by favoring ACE2 conformation. However, the impact on viral replication is not clear. There is evidence for enhancing effects of immune complexes on Fcγ receptor-mediated effector mechanisms and cytokine secretion after modulation of cell signaling in immune cells, specially by antibodies with altered glycosylation, which points to ADE that can contribute to COVID-19 pathology. However, more studies are needed to determine the impact of antibodies both in naturally infected and vaccinated subjects, which can lead to their use as a prognostic marker and increase vaccine safety.